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Chorea and Other Hyperkinetic Disorders
Chorea and Other Hyperkinetic Disorders DJ Brooks, Imperial College London and Aarhus University Denmark ã 2015 Elsevier Inc. All rights reserved.
Definitions Chorea is a condition that causes involuntary, unpredictable body movements that do not have a pattern. Distal chorea can appear as flicking movements of the fingers and feet and fidgeting. Proximal limb causes profound, uncontrolled movements of the arms and legs known as ballism or writhing movements of the trunk and limb, previously termed athetosis. Chorea can be caused by neurodegenerative disorders such as Huntington’s disease (HD); Huntington’s disease-like syndromes (HDLs) such as HDL2 caused by a cytosine thymidine guanine (CTG) expansion in the JPH3 gene, SCA17; neuroacanthocytosis (NA); and benign familial chorea (BFC). It can also be associated with the inflammatory disorders such as systemic lupus erythematosus (SLE) and postinfective Sydenham’s chorea, exposure to neuroleptic drugs and anticholinergics, and metabolic disorders such as hypoglycemia and Wilson’s disease. Dystonia is a disorder characterized by involuntary muscle spasms (contractions) that cause slower repetitive movements or abnormal postures generally on attempted action. Fixed dystonic posturing can be seen, particularly, after brain or limb injury. The movements may be painful, and some individuals with dystonia may have a postural or resting tremor, which can lead to confusion with Parkinson’s disease. Dystonia may affect only one muscle (focal), groups of muscles (segmental), or muscles throughout the body (generalized). Many forms of dystonia are genetic and a number of genes have now been characterized; however, the cause in the majority of cases is still not known.
The Role of Structural Imaging With the advent of higher-field magnetic resonance imaging (MRI), volumetric acquisitions coupled with voxel-based morphometry (VBM), and diffusion tensor sequences, the role of structural imaging in hyperkinetic disorders has become important. Using conventional T1- and T2-weighted sequences, MRI can help exclude acquired structural lesions or vascular disease as a cause of chorea or dystonia. Secondary dystonias may be associated with tumors, vascular disease, or toxic necrosis involving the lentiform nucleus or posterior thalamus (Bhatia & Marsden, 1994; Marsden, Obeso, Zarranz, & Lang, 1985). MRI signal changes, generally manifested as raised T2weighted signal, detect the cystic degeneration present in the lentiform nucleus, brain stem nuclei, and cerebellum of patients with established neurological Wilson’s disease (Starosta-Rubinstein et al., 1987). Volumetric MRI in association with VBM can now sensitively detect atrophy that may not be apparent visually or applying conventional region of interest analysis. Diffusion tensor imaging (DTI) measures the directionality (anisotropy) and amplitude of water flow along neuronal fibers and can reveal degeneration of white matter
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tracts and a loss of structural connectivity. Diffusion kurtosis imaging looking at the deviation of water flow rates from a Gaussian distribution is highly sensitive to changes in neurite density.
HD and Its Mimics HD is an autosomal dominantly transmitted disorder associated with an excess of cytosine adenosine guanine (CAG) triplet repeats (>38) in the huntingtin (HTT) gene on chromosome 4 resulting in a lengthened polyglutamine tail on huntingtin protein. The function of the HTT gene is still uncertain, but the pathology of HD targets medium spiny projection neurons in the striatum causing intranuclear and cytoplasmic inclusions of huntingtin to form. The pathology generally manifests as generalized choreiform movements in middle age though can present as a senile chorea. The involuntary movements are later accompanied by personality change, depression, and anxiety and, at end-stage, parkinsonism, dementia, and psychosis. Young-onset HD (the Westphal variant) is associated with a severe nonlevodoparesponsive akinetic rigid syndrome and chorea is less evident. Up to 7% of cases thought to have HD turn out to have an HDL syndrome due to an alternative genetic mutation (Wild et al., 2008). HDL2 is caused by a CTG expansion in the JPH3 gene coding for junctophilin-3 causing ubiquitin-immunoreactive intranuclear inclusions to form in the cortex and neuronal loss in the striatum and cortex. HDL4 is a more common HD-like syndrome in Caucasian populations and is a choreic phenotype of spinocerebellar ataxia type 17 (SCA17). HDL4 occurs in middle age and, like HD, is an autosomal dominant trinucleotide-repeat disorder affecting the TBP gene that encodes the TATA box binding protein. In most families, SCA17 manifests as an SCA but an HD-like presentation can occasionally be observed. Neuroferritinopathy is an autosomal dominant disorder presenting in middle age with generalized chorea or dystonia that progresses along with cognitive deterioration. Molecular genetic testing for mutations in the FTL gene, coding for the ferritin light chain, confirms the diagnosis and MRI shows abnormal iron accumulation in the basal ganglia manifesting as reduced T2weighted signal (McNeill et al., 2012; Schipper, 2012). Dentatorubropallidoluysian atrophy (DRPLA) can also cause choreic syndrome – particularly in the Japanese. Other degenerative causes of chorea and dystonia include NA, an autosomal recessive disorder caused by mutations in the VPS13A gene coding for chorein, and pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene coding for pantothenate kinase. NA is associated with self-mutilation and a peripheral neuropathy. PKAN causes early-onset dystonia and parkinsonism and was previously known as Hallervorden–Spatz disease. MRI characteristically reveals the eye-of-the-tiger sign with decreased striatal and increased pallidal T2-weighted signal (Hayflick, Hartman, Coryell, Gitschier, & Rowley, 2006).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00086-5
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MRI in HD There have now been many papers reporting the detection of reduced caudate and putamen volumes in symptomatic HD (Aylward et al., 2000; Georgiou-Karistianis, Scahill, Tabrizi, Squitieri, & Aylward, 2013). The reductions in caudate volume have been shown to correlate with the length of the CAG repeat expansion (Ruocco, Lopes-Cendes, Li, Santos-Silva, & Cendes, 2006) and rates of decline of cognitive function (Harrington et al., 2014). Along with striatal degeneration, pallidal, thalamic, and cortical volume loss can also be detected in symptomatic HD though cortical involvement is variable (Aylward et al., 1998; Nopoulos et al., 2010). Caudate volume loss can also be detected in premanifesting HD and has been reported to correlate with the estimated time of disease onset based on the CAG expansion length (Aylward et al., 1996). Using VBM, it has been shown that striatal volumes in premanifesting HD correlate with protrusion of tongue force, tapping accuracy to a metronome, and errors in antisaccade production (Scahill et al., 2013). Precuneus atrophy was associated with impaired recognition of facial emotions in photographs. The availability of diffusion-weighted and tensor imaging has now become widespread, and this modality has proved to be very sensitive to the presence of structural damage. In symptomatic HD, changes in motor striatum water diffusivity have been reported to correlate with disease severity when rated with the Unified Huntington’s Disease Rating Scale (UHDRS) (Bohanna et al., 2011). In another series of early symptomatic HD cases (Delmaire et al., 2013), mean diffusivity in the anterior putamen and head of caudate nucleus correlated with impairments in self-paced finger tapping, impairment of sense of smell rated with the University of Pennsylvania Smell Identification Test (UPSIT), and performance on Trail Making Tests. Reductions in cortical fractional anisotropy and increases in cortical mean water diffusivity have also been linked to clinical deficits in early HD (Tabrizi et al., 2009). In one series (Delmaire et al., 2013), patients showed significant correlations between the following: (a) accuracy of self-paced tapping and mean diffusivity in the parietal and prefrontal areas; (b) impairment of the sense of smell rated with the UPSIT and water diffusivity in the parietal and median temporal lobes, cingulate, and insula and reductions in fractional anisotropy in the insula and the external capsule; (c) performance on the Trail Making Test part B (a measure of executive function) and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal, and postcentral areas; and (d) the levels of apathy and reduced fractional anisotropy in the white matter of the rectus gyrus.
uncertain. A second familial cause of generalized dystonia is DYT6 due to mutations in the THAP1 gene on chromosome 8p. THAP1 is a DNA binding transcription factor that regulates the promoter of TOR1A, and mutations of this gene result in phenotypes that overlap with the DYT1 phenotypes. DYT6 has a 60% penetrance and generally presents as an adult-onset craniocervical or focal dystonia but occasionally manifests in childhood as a generalized dystonia. Conventional T1- and T2-weighted MRIs show no significant abnormalities in the genetic dystonias though cases of acquired dystonia can show caudate, putamen, globus pallidus, and posterior thalamus signal changes (Bhatia & Marsden, 1994). This has led to the suggestion that torsion dystonia arises due to a reduced inhibitory output from the basal ganglia to ventral thalamus causing premotor areas to become inappropriately overactive. However, more recent DTI studies in the genetic dystonias have implicated a primary role for the cerebellum in this disorder. Tractography with DTI has demonstrated tract malformations in DYT1 and DYT6. The process takes a target nucleus as a seed and then probabilistically constructs white matter tracts connecting the seed to other structures from measures of the amplitude and directionality of water proton diffusivity at a voxel level. In the dystonia associated with DYT1 mutations, abnormal structural connectivities between the cerebellar nuclei, pons, and thalamus and between the striatum and premotor cortex have been demonstrated with tractography (see Figure 1) (Carbon & Eidelberg, 2009; Niethammer, Carbon, Argyelan, & Eidelberg, 2011). Nonmanifesting DYT1 carriers showed severe disruption of both cerebellar–pontine–thalamic and striato–sensorimotor cortex connections while manifesting carriers showed relatively preserved striatofrontal connections. These workers hypothesized that dystonia arises primarily from aberrant transmission in cerebellar–thalamic rather than basal ganglia projections and that the presence of striatofrontal connection disruption was protective, blocking dysfunctional effects arising from the altered cerebellar output (Niethammer et al., 2011). Deep brain stimulation of the internal pallidum may act to improve genetic dystonia by depressing basal ganglia output to the motor cortex and so inducing a blockade of the aberrant cerebellar–thalamic transmission.
MRI in Dystonia The most common familial form of generalized dystonia (DYT1) is an autosomal dominant disorder associated with a TOR1A gene mutation on chromosome 9q34. It has around a 30% penetrance and is generally early-onset, starting in the lower limb. The genetic mutation is a GAG deletion within the coding region of the gene responsible for torsin A, an ATPbinding chaperone protein whose exact function is still
Controls (n = 7)
DYT1 (n = 7)
Figure 1 Reduced cerebellar–thalamic and striatofrontal connections on tractography in DYT1 dystonia. Reproduced from Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., & Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia. Neurology, 72(24), 2097–2103.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
Functional Imaging Functional imaging provides a means of detecting and characterizing the regional changes in human brain metabolism and receptor binding associated with hyperkinetic movement disorders. In genetic choreas and dystonias, the major role of functional imaging is to throw light on the pathophysiology underlying involuntary movements and to detect evidence of disease activity in at-risk subjects. Functional imaging provides a sensitive means of detecting active subclinical disease and an objective biomarker of disease progression and in principle could determine whether this is influenced by novel neuroprotective strategies. There are four main approaches to functional imaging: positron emission tomography (PET) has high sensitivity, being able to detect femtomolar levels of positron-emitting radioisotopes at a spatial resolution of 2–3 mm in humans. It allows quantitative in vivo examination of alterations in regional cerebral blood flow (rCBF), glucose, and oxygen metabolism, enzyme activities, and brain surface receptor binding. Brain inflammation, evidenced as translocator protein (TSPO) expression by activated microglia, can be detected in patients with both neurodegenerative and inflammatory disorders. Single-photon emission computed tomography (SPECT) is less sensitive but more widely available than PET and can provide measures of rCBF and receptor binding. Magnetic resonance spectroscopy (MRS) has lower sensitivity and spatial resolution than radioisotope imaging approaches, detecting metabolite levels (N-acetylaspartate, lactate, phospholipids, and ATP) in the millimolar range at a 1 cm spatial resolution. Finally, using the blood oxygen level-dependent (BOLD) technique to detect local changes in venular oxygenation, MRI can detect activation-induced flow changes over a timescale of seconds when subjects perform tasks. Brain regions that are functionally interconnected show synchronization of slow oscillations in their venular oxygenation when BOLD sequences are run under resting conditions. This allows networks subserving attention, executive, and motor function to be delineated with resting fMRI and covariance analysis and their disruption by involuntary movement disorders to be demonstrated.
Functional Imaging of Choreas While the neurodegenerative disorders HD, HDL syndromes, NA, DRPLA, and BFC are all associated with chorea, it can also be a feature of inflammatory disorders such as the vasculitis SLE and poststreptococcal infection (Sydenham’s chorea). Chronic dopamine D2 receptor blockade by exposure to neuroleptics or vestibular sedatives can result in tardive chorea. Clinically manifesting HD patients show severely reduced levels of resting glucose and oxygen metabolism of their caudate and lentiform nuclei (Hayden et al., 1986; Kuhl et al., 1982; Leenders, Frackowiak, Quinn, & Marsden, 1986). Levels of resting putamen metabolism correlate with locomotor function while caudate metabolism correlates with performance on executive tests sensitive to frontal lobe function (Berent et al., 1988; Young et al., 1986). In early HD, cortical metabolism is preserved but as the disease progresses and dementia becomes
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prominent, it declines, the frontal cortex being particularly targeted (Kuwert, Lange, Langen, Herzog, Aulich, et al., 1990). Caudate hypometabolism, however, is not specific to HD, being seen in NA, DRPLA, and cases of BFC (Dubinsky, Hallett, Levey, & Di Chiro, 1989; Hosokawa et al., 1987; Kuwert, Lange, Langen, Herzog, Hefter, et al., 1990; Suchowersky et al., 1986). In contrast, striatal glucose metabolism is normal or elevated in inflammatory choreas (Guttman et al., 1987; Weindl et al., 1993) and also in tardive dyskinesia (Andersson et al., 1990; Pahl, Mazziotta, Bartzokis, Cummings, Altschuler, et al., 1987) discriminating these disorders from the degenerative choreas. Regional cerebral metabolism in HD has been studied with proton MRS. N-Acetylaspartate levels in the basal ganglia are reduced in manifesting patients, whereas lactate levels in the basal ganglia and cortex are elevated, suggesting that mitochondrial dysfunction is a component of this disorder (Jenkins, Koroshetz, Beal, & Rosen, 1993). Lactate levels have been reported to be normal in asymptomatic gene carriers, suggesting that the mitochondrial dysfunction seen in HD represents an associated secondary rather than a causative event. The medium spiny striatal neurons that degenerate in HD express surface dopamine D1, D2, opioid, cannabinoid CB1, and benzodiazepine receptors. PET and SPECT studies with benzamide- and spiperone-based tracers have reported that striatal D2 binding is reduced on average by 60% in manifesting HD gene carriers and by at least 30% at the onset of clinical symptoms (Antonini et al., 1996; Brucke et al., 1991; Turjanski, Weeks, Dolan, Harding, & Brooks, 1995). 11CSCH23390 PET studies in HD have demonstrated reduced D1 binding in both the striatum and temporal cortex (Karlsson et al., 1994). Turjanski et al. (1995) used 11C-SCH23390 and 11 C-raclopride PET to study both D1 binding and D2 binding in HD. They found a parallel reduction in striatal binding to these receptor subtypes irrespective of choreic or rigid phenotype, reductions in D1 and D2 binding both correlating with the severity of rigidity rather than chorea. Striatal opioid (Weeks et al., 1997), CB1 (Van Laere et al., 2010), and benzodiazepine (Holthoff et al., 1993) binding have also been shown to be reduced in clinically affected HD patients. Reductions are smaller, however, compared to the loss of dopamine receptors. Reduced striatal dopamine receptor binding can also be seen in other degenerative choreas and a mean 70% reduction of striatal 11C-raclopride binding has been reported in NA (Brooks et al., 1991). In contrast, normal striatal D2 binding has been reported in SLE chorea (Turjanski et al., 1995) and tardive dyskinesia (Andersson et al., 1990; Blin et al., 1989 Nov). This finding argues against the hypothesis that tardive dyskinesia (TD) results from striatal D2 receptor supersensitivity following prolonged exposure to neuroleptics. Postmortem studies have reported downstream reductions in pallidal and subthalamic gamma aminobutyric acid (GABA) levels that may act to disinhibit basal ganglia output to the cortex (Andersson et al., 1989). As manifesting HD patients show at least a 30% loss of striatal dopamine receptor binding and glucose metabolism at symptom onset, 11C-SCH23390, 11C-raclopride, and 18 FDG (2-fluoro-2-deoxyglucose) PET should all be capable
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of detecting subclinical dysfunction in premanifesting HD gene carriers. A significant parallel loss of striatal D1 and D2 binding in four of eight premanifesting HD gene carriers has been reported (Weeks, Piccini, Harding, & Brooks, 1996), while reduced caudate glucose metabolism was noted in 9 out of 12 and 3 out of 8 asymptomatic adult HD gene carriers in two other series (Grafton et al., 1990; Hayden, Hewitt, Martin, Clark, & Amman, 1987). Functional imaging has been used to determine the rate of progression of HD. FDG PET has shown a 3.1% annual decline in caudate glucose metabolism in manifesting HD patients (Grafton et al., 1992) while 11C-raclopride PET revealed an annual 6% change in striatal D2 binding (Antonini, Leenders, & Eidelberg, 1998 Feb). An annual 3–4% loss of striatal D1 and D2 binding was detected in manifesting HD gene carriers and a 6% loss in those 50% of adult premanifesting HD gene carriers where disease was subclinically active (Andrews et al., 1999). 11 C-raclopride PET has also detected early loss of frontal D2 binding in HD (Pavese et al., 2002). These findings all suggest that functional imaging provides an objective means of following HD progression and could be a marker of efficacy when testing putative neuroprotective or restorative interventions.
Imaging Inflammation in HD The microglia constitute 10–20% of white cells in the brain and form its natural defense mechanism. They are normally in a resting state, but local injury causes them to activate and swell, expressing human leukocyte antigen (HLA) antigens on the cell surface and releasing cytokines and growth factors. The mitochondria of activated but not resting microglia express the TSPO, which is a steroid and anion transporter and helps regulate membrane potential. The TSPO was previously known as the peripheral benzodiazepine receptor although it does not possess classical receptor properties. 11C-PK11195 is an isoquinoline derivative that binds selectively to an isoquinoline site on the TSPO and so provides an in vivo PET marker of the level and spatial extent of microglial activation. Postmortem studies of HD brains have shown a significant accumulation of activated microglia in the basal ganglia and the frontal cortex (Sapp et al., 2001). Manifesting HD patients show increased striatal 11C-PK11195 binding, the levels of which correlate with clinical disease severity scored with the UHDRS (Pavese et al., 2005). Levels of striatal microglial activation also correlate with striatal reductions in 11C-raclopride binding (see Figure 2) and with the size of the patients’ CAG triplet expansion suggesting that microglial activation plays a role in driving the neurodegenerative process. Increased striatal 11 C-PK11195 binding can be detected with 11C-PK11195 PET in a majority of adult premanifesting HD gene carriers and also cortical binding if statistical parametric mapping is employed (Tai et al., 2007). This suggests that microglial activation is an early event in HD and its suppression could be therapeutically beneficial.
Functional Imaging of Dystonia FDG PET has shown that DYT1 carriers have regional brain levels of resting glucose metabolism in the normal range.
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Microglial activation 11C-PK11195
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Figure 2 11C-PK11195 and 11C-raclopride PET scans of a healthy subject and HD gene carrier. Significantly raised microglial activation is evident in the frontal cortex and striata of the HD patient along with reductions in striatal D2 binding. Courtesy of Dr. Thomasin Andrews.
However, covariance analysis between regional and voxel levels of rCMRGlc reveals an abnormal resting metabolic profile where posterior lentiform nucleus, thalamic, and supplementary motor area glucose metabolism is relatively raised (Carbon & Eidelberg, 2009). This torsion dystonia-related profile (TDRP) is seen whether DYT1 gene carriers are manifesting or premanifesting. A PET study on blepharospasm patients performed while they were asleep also showed this abnormal profile of resting glucose metabolism confirming that it is not simply related to involuntary movements (Hutchinson et al., 2000). Manifesting DYT6 dystonias show a similar TDRP to DYT1 cases (Carbon et al., 2004). These findings suggest that overactivity of a common network involving the basal ganglia and frontal cortex may underlie all the genetic dystonias. Manifesting DYT1 carriers were shown to have relatively higher levels of metabolism in the pre-supplementary motor area (pre-SMA) and parietal association cortices and lower levels in the inferior cerebellum, brain stem, and ventral thalamus compared with nonmanifesting carriers (Carbon, Argyelan, & Eidelberg, 2010). This finding would fit with the view that abnormal sensorimotor integration underlies these involuntary movements. 18 F-dopa PET and 123I-beta-CIT SPECT studies have shown normal striatal dopamine terminal function in the majority of idiopathic dystonia cases (Naumann et al., 1998; Playford, Fletcher, Sawle, Marsden, & Brooks, 1993). In contrast, PET and SPECT have shown that striatal D2 binding is significantly reduced (Naumann et al., 1998; Perlmutter et al., 1997). In one 11 C-raclopride PET series, DYT1 carriers had a mean 15% and DYT6 carriers a mean 38% reduction in striatal D2 binding regardless of clinical penetrance (Figure 3) (Carbon et al., 2009). Reductions in striatal D2 expression could result in decreased activity of the indirect striatopallidal pathway, which normally acts to inhibit unwanted movement or actions. Recently, it has been reported that uptake of 11Cflumazenil, a marker of benzodiazepine receptor binding on the GABAA complex, is reduced in motor and premotor areas in a group of DYT1 and sporadic dystonias (Garibotto et al.,
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INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
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Figure 3 Loss of striatal and thalamic dopamine D2 binding in DYT1 dystonia. Reproduced from Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., & Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia. Neurology, 72(24), 2097–2103.
2011). Such a deficit in GABAergic function could result in a failure of normal cortical inhibitory circuits.
Motor Activation in Dystonia Cerebral activation studies in idiopathic torsion dystonia have suggested an imbalance between sensorimotor and premotor cortex functions. If dystonia patients perform paced joystick movements with their right hands in freely selected directions, they show significantly increased levels of contralateral putamen, rostral supplementary motor area, lateral premotor cortex, and dorsolateral prefrontal area activation (CeballosBaumann et al., 1995). In contrast, activation of contralateral sensorimotor cortex and caudal SMA is impaired; these are the motor cortical areas that send direct pyramidal tract projections to the spinal cord. Attenuation of sensorimotor cortex and caudal SMA activation in generalized and focal dystonia during vibrotactile stimulation have also been reported (Tempel & Perlmutter, 1990, 1993). Abnormal overactivation of premotor and parietal areas and the cerebellum has been demonstrated during sequence learning in nonmanifesting DYT1 carriers despite their impaired performance on the task (Carbon et al., 2008).
Dopamine-Responsive Dystonia and Dystonia–Parkinsonism Dominantly inherited dopamine-responsive dystonia (DRD) is related to a mutation in the DYT5 gene coding for GTP cyclohydrolase 1. This enzyme constitutes part of the tetrahydrobiopterin synthetic pathway, the cofactor for tyrosine hydroxylase. Patients are unable to manufacture levodopa, and hence dopamine, from endogenous tyrosine but can still convert exogenous
levodopa to dopamine. DRD cases generally present in childhood with diurnally fluctuating dystonia and later develop background parkinsonism. Occasionally, the condition presents as pure parkinsonism in adulthood. 18F-dopa PET and 123I-betaCIT SPECT findings are normal in DRD patients (Naumann et al., 1997; Sawle et al., 1991), distinguishing this condition from early-onset dystonia–parkinsonism where severely reduced putamen 18F-dopa and 123I-beta-CIT uptake is seen (Turjanski et al., 1993).
Conclusions Structural and functional imaging can sensitively detect evidence of disease activity in HD gene carriers a decade before symptoms manifest. Both modalities could be used to track disease progression and to determine the efficacy of potential neuroprotective and restorative interventions. The inflammatory- and drug-related choreas can be discriminated from degenerative choreas by their preservation of striatal metabolism and receptor binding. DTI detects abnormal cerebellar–thalamic and premotor– striatal connectivity in the genetic dystonias, the first causing and the second possibly acting to suppress disease manifestation. PET reveals a common abnormal resting profile of increased lentiform nucleus and premotor glucose metabolism underlying the genetic dystonias. Reduced striatal D2 binding and cortical benzodiazepine receptor binding are also seen, which could contribute to the premotor cortical disinhibition associated with these involuntary movements.
References Andersson, U., Eckernas, S. A., Hartvig, P., Ulin, J., Langstrom, B., & Haggstrom, J. E. (1990). Striatal binding of 11c-NMSP studied with positron emission tomography
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in patients with persistent tardive dyskinesia: No evidence for altered dopamine receptor binding. Journal of Neural Transmission, 79, 215–226. Andersson, U., Haggstrom, J.-E., Levin, E. D., Bondesson, U., Valverius, M., & Gunne, L. M. (1989). Reduced glutamate decarboxylase activity in the subthalamic nucleus of patients with tardive dyskinesia. Movement Disorders, 4, 37–46. Andrews, T. C., Weeks, R. A., Turjanski, N., Gunn, R. N., Watkins, L. H. A., Sahakian, B., et al. (1999). Huntington’s disease progression pet and clinical observations. Brain, 122, 2353–2363. Antonini, A., Leenders, K. L., & Eidelberg, D. (1998). [C-11]Raclopride-pet studies of the Huntington’s disease rate of progression: Relevance of the trinucleotide repeat length. Annals of Neurology, 43(2), 253–255. Antonini, A., Leenders, K. L., Spiegel, R., Meier, D., Vontobel, P., Weigell Weber, M., et al. (1996). Striatal glucose metabolism and dopamine D-2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain, 119, 2085–2095. Aylward, E. H., Anderson, N. B., Bylsma, F. W., Wagster, M. V., Barta, P. E., Sherr, M., et al. (1998). Frontal lobe volume in patients with Huntington’s disease. Neurology, 50(1), 252–258. Aylward, E. H., Codori, A. M., Barta, P. E., Pearlson, G. D., Harris, G. J., & Brandt, J. (1996). Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Archives of Neurology, 53(12), 1293–1296. Aylward, E. H., Codori, A. M., Rosenblatt, A., Sherr, M., Brandt, J., Stine, O. C., et al. (2000). Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Movement Disorders, 15(3), 552–560. Berent, S., Giordani, B., Lehtinen, S., Markel, D., Penney, J. B., Buchtel, H. A., et al. (1988). Positron emission tomographic scan investigations of Huntington’s disease – cerebral metabolic correlates of cognitive function. Annals of Neurology, 23, 541–546. Bhatia, K. P., & Marsden, C. D. (1994). The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain, 117, 859–876. Blin, J., Baron, J. C., Cambon, H., Bonnet, A. M., Dubois, B., Loc’h, C., et al. (1989 Nov). Striatal dopamine D2 receptors in tardive dyskinesia: Pet study. Journal of Neurology, Neurosurgery, and Psychiatry, 52(11), 1248–1252. Bohanna, I., Georgiou-Karistianis, N., Sritharan, A., Asadi, H., Johnston, L., Churchyard, A., et al. (2011). Diffusion tensor imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits. Brain Imaging and Behavior, 5(3), 171–180. Brooks, D. J., Ibanez, V., Playford, E. D., Sawle, G. V., Leigh, P. N., Kocen, R. S., et al. (1991). Presynaptic and postsynaptic striatal dopaminergic function in neuroacanthocytosis: A positron emission tomographic study. Annals of Neurology, 30, 166–171. Brucke, T., Podreka, I., Wenger, S., Angelberger, P., Muller, C., Walter, H., et al. (1991). Dopamine receptor imaging with SPECT: A diagnostic tool in extrapyramidal disorders and in vivo assay for the measurement of receptor blockade by neuroleptic treatment. Journal of Cerebral Blood Flow and Metabolism, 11(Suppl. 2), S877. Carbon, M., Argyelan, M., & Eidelberg, D. (2010). Functional imaging in hereditary dystonia. European Journal of Neurology, 17(Suppl. 1), 58–64. Carbon, M., & Eidelberg, D. (2009). Abnormal structure-function relationships in hereditary dystonia. Neuroscience, 164(1), 220–229. Carbon, M., Ghilardi, M. F., Argyelan, M., Dhawan, V., Bressman, S. B., & Eidelberg, D. (2008). Increased cerebellar activation during sequence learning in DYT1 carriers: An equiperformance study. Brain, 131(Pt 1), 146–154. Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotyperelated features of dystonia. Neurology, 72(24), 2097–2103. Carbon, M., Su, S., Dhawan, V., Raymond, D., Bressman, S., & Eidelberg, D. (2004). Regional metabolism in primary torsion dystonia: Effects of penetrance and genotype. Neurology, 62(8), 1384–1390. Ceballos-Baumann, A. O., Passingham, R. E., Warner, T., Playford, E. D., Marsden, C. D., & Brooks, D. J. (1995). Overactivity of rostral and underactivity of caudal frontal areas in idiopathic torsion dystonia: A Pet activation study. Annals of Neurology, 37, 363–372. Delmaire, C., Dumas, E. M., Sharman, M. A., van den Bogaard, S. J., Valabregue, R., Jauffret, C., et al. (2013). The structural correlates of functional deficits in early Huntington’s disease. Human Brain Mapping, 34(9), 2141–2153. Dubinsky, R. M., Hallett, M., Levey, R., & Di Chiro, G. (1989). Regional brain glucose metabolism in neuroacanthocytosis. Neurology, 39, 1253–1255. Garibotto, V., Romito, L. M., Elia, A. E., Soliveri, P., Panzacchi, A., Carpinelli, A., et al. (2011). In vivo evidence for GABA(a) receptor changes in the sensorimotor system in primary dystonia. Movement Disorders, 26(5), 852–857. Georgiou-Karistianis, N., Scahill, R., Tabrizi, S. J., Squitieri, F., & Aylward, E. (2013). Structural MRI in Huntington’s disease and recommendations for its potential use in clinical trials. Neuroscience and Biobehavioral Reviews, 37(3), 480–490.
Grafton, S. T., Mazziotta, J. C., Pahl, J. J., St George Hyslop, P., Haines, J. L., Gusella, J., et al. (1992). Serial changes of glucose cerebral metabolism and caudate size in persons at risk for Huntington’s disease. Archives of Neurology, 49, 1161–1167. Grafton, S. T., Mazziotta, J. C., Pahl, J. J., St. George-Hyslop, P., Haines, J. L., Gusella, J., et al. (1990). A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington’s disease. Annals of Neurology, 28, 614–621. Guttman, M., Lang, A. E., Garnett, E. S., Nahmias, C., Firnau, G., Tyndal, F. J., et al. (1987). Regional cerebral glucose metabolism in SLE chorea: Further evidence that striatal hypometabolism is not a correlate of chorea. Movement Disorders, 2, 201–210. Harrington, D. L., Liu, D., Smith, M. M., Mills, J. A., Long, J. D., Aylward, E. H., et al. (2014). Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain and Behavior, 4(1), 29–40. Hayden, M. R., Hewitt, J., Martin, W. R. W., Clark, C., & Amman, A. (1987). Studies in persons at risk for Huntington’s disease. The New England Journal of Medicine, 317, 382–383. Hayden, M. R., Martin, W. R. W., Stoessl, A. J., Clark, C., Hollenberg, S., Adam, M. J., et al. (1986). Positron emission tomography in the early diagnosis of Huntington’s disease. Neurology, 36, 888–894. Hayflick, S. J., Hartman, M., Coryell, J., Gitschier, J., & Rowley, H. (2006). Brain MRI in neurodegeneration with brain iron accumulation with and without Pank2 mutations. AJNR - American Journal of Neuroradiology, 27(6), 1230–1233. Holthoff, V. A., Koeppe, R. A., Frey, K. A., Penney, J. B., Markel, D. S., Kuhl, D. E., et al. (1993). Positron emission tomography measures of benzodiazepine receptors in Huntington’s disease. Annals of Neurology, 34, 76–81. Hosokawa, S., Ichiya, Y., Kuwabara, Y., Ayabe, Z., Mitsuo, K., Goto, I., et al. (1987). Positron emission tomography in cases of chorea with different underlying diseases. Journal of Neurology, Neurosurgery, and Psychiatry, 50, 1284–1287. Hutchinson, M., Nakamura, T., Moeller, J. R., Antonini, A., Belakhlef, A., Dhawan, V., et al. (2000). The metabolic topography of essential blepharospasm: A focal dystonia with general implications. Neurology, 55(5), 673–677. Jenkins, B. G., Koroshetz, W. J., Beal, M. F., & Rosen, B. R. (1993). Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localised 1 h NMR spectroscopy. Neurology, 43, 2689–2695. Karlsson, P., Lundin, A., Anvret, M., Suhara, T., Halldin, C., & Farde, L. (1994). Dopamine D1 receptor number – A sensitive PET marker for early brain degeneration in Huntington’s disease. European Archives of Psychiatry and Neurological Sciences, 243, 249–255. Kuhl, D. E., Phelps, M. E., Markham, C. H., Metter, E. J., Riege, W. H., & Winter, E. J. (1982). Cerebral metabolism and atrophy in Huntington’s disease determined by 18 FDG and computed tomographic scans. Annals of Neurology, 12, 425–434. Kuwert, T., Lange, H. W., Langen, K. J., Herzog, H., Aulich, A., & Feinendegen, L. E. (1990). Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain, 113, 1405–1423. Kuwert, T., Lange, H. W., Langen, K. J., Herzog, H., Hefter, H., Aulich, A., et al. (1990). Normal striatal glucose consumption in two patients with benign hereditary chorea as measured by positron emission tomography. Journal of Neurology, 237, 80–84. Leenders, K. L., Frackowiak, R. S.J, Quinn, N., & Marsden, C. D. (1986). Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Movement Disorders, 1, 69–77. Marsden, C. D., Obeso, J. A., Zarranz, J. J., & Lang, A. E. (1985). The anatomical basis of symptomatic hemidystonia. Brain, 108, 463–483. McNeill, A., Gorman, G., Khan, A., Horvath, R., Blamire, A. M., & Chinnery, P. F. (2012). Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate. AJNR - American Journal of Neuroradiology, 33(9), 1810–1813. Naumann, M., Pirker, W., Reiners, K., Lange, K., Becker, G., & Brucke, T. (1997). [123i] Beta-Cit single-photon emission tomography in dopa-responsive dystonia. Movement Disorders, 12(3), 448–451. Naumann, M., Pirker, W., Reiners, K., Lange, K. W., Becker, G., & Brucke, T. (1998). Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: A SPECT study using [123i]epidepride and [123i]BCIT. Movement Disorders, 13, 319–323. Niethammer, M., Carbon, M., Argyelan, M., & Eidelberg, D. (2011). Hereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging. Neurobiology of Disease, 42(2), 202–209. Nopoulos, P. C., Aylward, E. H., Ross, C. A., Johnson, H. J., Magnotta, V. A., Juhl, A. R., et al. (2010). Cerebral cortex structure in prodromal Huntington disease. Neurobiology of Disease, 40(3), 544–554. Pahl, J. J., Mazziotta, J. C., Bartzokis, G., Cummings, J., Altschuler, L., Mintz, J., et al. (1995). Positron-emission tomography in tardive dyskinesia. The Journal of Neuropsychiatry and Clinical Neurosciences, 7, 457–465.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., et al. (2005). Activated microglia accompany neuronal dysfunction in Huntington’s disease. An C-11-raclopride and C-11-(R)-Pk11195 PET study. Neurology, 64(6), A91. Pavese, N., Rosser, A. E., Brooks, D. J., Barker, R. A., Dunnett, S. B., & Piccini, P. (2002). Cortical dopamine D2 receptor dysfunction in Huntington’s disease. Movement Disorders, 17, P1050. Perlmutter, J. S., Stambuk, M. K., Markham, J., Black, K. J., McGee-Minnich, L., Jankovic, J., et al. (1997). Decreased [F-18] spiperone binding in putamen in idiopathic focal dystonia. Journal of Neuroscience, 17, 843–850. Playford, E. D., Fletcher, N. A., Sawle, G. V., Marsden, C. D., & Brooks, D. J. (1993). Integrity of the nigro-striatal dopaminergic system in familial dystonia: An 18f-dopa PET study. Brain, 116, 1191–1199. Ruocco, H. H., Lopes-Cendes, I., Li, L. M., Santos-Silva, M., & Cendes, F. (2006). Striatal and extrastriatal atrophy in Huntington’s disease and its relationship with length of the CAG repeat. Brazilian Journal of Medical and Biological Research, 39(8), 1129–1136. Sapp, E., Kegel, K. B., Aronin, N., Hashikawa, T., Uchiyama, Y., Tohyama, K., et al. (2001). Early and progressive accumulation of reactive microglia in the Huntington disease brain. Journal of Neuropathology and Experimental Neurology, 60(2), 161–172. Sawle, G. V., Leenders, K. L., Brooks, D. J., Harwood, G., Lees, A. J., Frackowiak, R. S. J., et al. (1991). Dopa-responsive dystonia: [18f]Dopa positron emission tomography. Annals of Neurology, 30, 24–30. Scahill, R. I., Hobbs, N. Z., Say, M. J., Bechtel, N., Henley, S. M., Hyare, H., et al. (2013). Clinical impairment in premanifest and early Huntington’s disease is associated with regionally specific atrophy. Human Brain Mapping, 34(3), 519–529. Schipper, H. M. (2012). Neurodegeneration with brain iron accumulation – clinical syndromes and neuroimaging. Biochimica et Biophysica Acta, 1822(3), 350–360. Starosta-Rubinstein, S., Young, A. B., Kluin, K., Hill, G., Aisen, A. M., Gabrielsen, T., et al. (1987). Clinical assessment of 31 patients with Wilson’s disease: Correlations with structural changes on magnetic resonance imaging. Archives of Neurology, 44, 365–370. Suchowersky, O., Hayden, M. R., Martin, W. R. W., Stoessl, A. J., Hildebrand, A. M., & Pate, B. D. (1986). Cerebral metabolism of glucose in benign hereditary chorea. Movement Disorders, 1, 33–45. Tabrizi, S. J., Langbehn, D. R., Leavitt, B. R., Roos, R. A., Durr, A., Craufurd, D., et al. (2009). Biological and clinical manifestations of Huntington’s disease in the
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longitudinal track-HD study: Cross-sectional analysis of baseline data. Lancet Neurology, 8(9), 791–801. Tai, Y. F., Pavese, N., Gerhard, A., Tabrizi, S. J., Barker, R. A., Brooks, D. J., et al. (2007). Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain, 130, 1759–1766. Tempel, L. W., & Perlmutter, J. S. (1990). Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia. Brain, 113, 691–707. Tempel, L. W., & Perlmutter, J. S. (1993). Abnormal cortical responses in patients with Writer’s cramp. Neurology, 43, 2252–2257. Turjanski, N., Bhatia, K., Burn, D. J., Sawle, G. V., Marsden, C. D., & Brooks, D. J. (1993). Comparison of striatal 18f-Dopa uptake in adult-onset dystoniaparkinsonism, Parkinson’s disease, and dopa-responsive dystonia. Neurology, 43, 1563–1568. Turjanski, N., Weeks, R., Dolan, R., Harding, A. E., & Brooks, D. J. (1995). Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas: A PET study. Brain, 118, 689–696. Van Laere, K., Casteels, C., Dhollander, I., Goffin, K., Grachev, I., Bormans, G., et al. (2010). Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine, 51(9), 1413–1417. Weeks, R. A., Cunningham, V. J., Piccini, P., Waters, S., Harding, A. E., & Brooks, D. J. (1997). 11c-Diprenorphine binding in Huntington’s disease: A comparison of region of interest analysis and statistical parametric mapping. Journal of Cerebral Blood Flow & Metabolism, 17, 943–949. Weeks, R. A., Piccini, P., Harding, A. E., & Brooks, D. J. (1996). Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington’s disease. Annals of Neurology, 40, 49–54. Weindl, A., Kuwert, T., Leenders, K. L., Poremba, M., Voneinsiedel, H. G., Antonini, A., et al. (1993). Increased striatal glucose consumption in Sydenham chorea. Movement Disorders, 8, 437–444. Wild, E. J., Mudanohwo, E. E., Sweeney, M. G., Schneider, S. A., Beck, J., Bhatia, K. P., et al. (2008). Huntington’s disease phenocopies are clinically and genetically heterogeneous. Movement Disorders, 23(5), 716–720. Young, A. B., Penney, J. B., Starosta-Rubinstein, S., Markel, D. S., Berent, S., Giordani, B., et al. (1986). PET scan investigations of Huntington’s disease: Cerebral metabolic correlates of neurological features and functional decline. Annals of Neurology, 20, 296–303.
Definitions Chorea is a condition that causes involuntary, unpredictable body movements that do not have a pattern. Distal chorea can appear as flicking movements of the fingers and feet and fidgeting. Proximal limb causes profound, uncontrolled movements of the arms and legs known as ballism or writhing movements of the trunk and limb, previously termed athetosis. Chorea can be caused by neurodegenerative disorders such as Huntington’s disease (HD); Huntington’s disease-like syndromes (HDLs) such as HDL2 caused by a cytosine thymidine guanine (CTG) expansion in the JPH3 gene, SCA17; neuroacanthocytosis (NA); and benign familial chorea (BFC). It can also be associated with the inflammatory disorders such as systemic lupus erythematosus (SLE) and postinfective Sydenham’s chorea, exposure to neuroleptic drugs and anticholinergics, and metabolic disorders such as hypoglycemia and Wilson’s disease. Dystonia is a disorder characterized by involuntary muscle spasms (contractions) that cause slower repetitive movements or abnormal postures generally on attempted action. Fixed dystonic posturing can be seen, particularly, after brain or limb injury. The movements may be painful, and some individuals with dystonia may have a postural or resting tremor, which can lead to confusion with Parkinson’s disease. Dystonia may affect only one muscle (focal), groups of muscles (segmental), or muscles throughout the body (generalized). Many forms of dystonia are genetic and a number of genes have now been characterized; however, the cause in the majority of cases is still not known.
The Role of Structural Imaging With the advent of higher-field magnetic resonance imaging (MRI), volumetric acquisitions coupled with voxel-based morphometry (VBM), and diffusion tensor sequences, the role of structural imaging in hyperkinetic disorders has become important. Using conventional T1- and T2-weighted sequences, MRI can help exclude acquired structural lesions or vascular disease as a cause of chorea or dystonia. Secondary dystonias may be associated with tumors, vascular disease, or toxic necrosis involving the lentiform nucleus or posterior thalamus (Bhatia & Marsden, 1994; Marsden, Obeso, Zarranz, & Lang, 1985). MRI signal changes, generally manifested as raised T2weighted signal, detect the cystic degeneration present in the lentiform nucleus, brain stem nuclei, and cerebellum of patients with established neurological Wilson’s disease (Starosta-Rubinstein et al., 1987). Volumetric MRI in association with VBM can now sensitively detect atrophy that may not be apparent visually or applying conventional region of interest analysis. Diffusion tensor imaging (DTI) measures the directionality (anisotropy) and amplitude of water flow along neuronal fibers and can reveal degeneration of white matter
Brain Mapping: An Encyclopedic Reference
tracts and a loss of structural connectivity. Diffusion kurtosis imaging looking at the deviation of water flow rates from a Gaussian distribution is highly sensitive to changes in neurite density.
HD and Its Mimics HD is an autosomal dominantly transmitted disorder associated with an excess of cytosine adenosine guanine (CAG) triplet repeats (>38) in the huntingtin (HTT) gene on chromosome 4 resulting in a lengthened polyglutamine tail on huntingtin protein. The function of the HTT gene is still uncertain, but the pathology of HD targets medium spiny projection neurons in the striatum causing intranuclear and cytoplasmic inclusions of huntingtin to form. The pathology generally manifests as generalized choreiform movements in middle age though can present as a senile chorea. The involuntary movements are later accompanied by personality change, depression, and anxiety and, at end-stage, parkinsonism, dementia, and psychosis. Young-onset HD (the Westphal variant) is associated with a severe nonlevodoparesponsive akinetic rigid syndrome and chorea is less evident. Up to 7% of cases thought to have HD turn out to have an HDL syndrome due to an alternative genetic mutation (Wild et al., 2008). HDL2 is caused by a CTG expansion in the JPH3 gene coding for junctophilin-3 causing ubiquitin-immunoreactive intranuclear inclusions to form in the cortex and neuronal loss in the striatum and cortex. HDL4 is a more common HD-like syndrome in Caucasian populations and is a choreic phenotype of spinocerebellar ataxia type 17 (SCA17). HDL4 occurs in middle age and, like HD, is an autosomal dominant trinucleotide-repeat disorder affecting the TBP gene that encodes the TATA box binding protein. In most families, SCA17 manifests as an SCA but an HD-like presentation can occasionally be observed. Neuroferritinopathy is an autosomal dominant disorder presenting in middle age with generalized chorea or dystonia that progresses along with cognitive deterioration. Molecular genetic testing for mutations in the FTL gene, coding for the ferritin light chain, confirms the diagnosis and MRI shows abnormal iron accumulation in the basal ganglia manifesting as reduced T2weighted signal (McNeill et al., 2012; Schipper, 2012). Dentatorubropallidoluysian atrophy (DRPLA) can also cause choreic syndrome – particularly in the Japanese. Other degenerative causes of chorea and dystonia include NA, an autosomal recessive disorder caused by mutations in the VPS13A gene coding for chorein, and pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder caused by mutations in the PANK2 gene coding for pantothenate kinase. NA is associated with self-mutilation and a peripheral neuropathy. PKAN causes early-onset dystonia and parkinsonism and was previously known as Hallervorden–Spatz disease. MRI characteristically reveals the eye-of-the-tiger sign with decreased striatal and increased pallidal T2-weighted signal (Hayflick, Hartman, Coryell, Gitschier, & Rowley, 2006).
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MRI in HD There have now been many papers reporting the detection of reduced caudate and putamen volumes in symptomatic HD (Aylward et al., 2000; Georgiou-Karistianis, Scahill, Tabrizi, Squitieri, & Aylward, 2013). The reductions in caudate volume have been shown to correlate with the length of the CAG repeat expansion (Ruocco, Lopes-Cendes, Li, Santos-Silva, & Cendes, 2006) and rates of decline of cognitive function (Harrington et al., 2014). Along with striatal degeneration, pallidal, thalamic, and cortical volume loss can also be detected in symptomatic HD though cortical involvement is variable (Aylward et al., 1998; Nopoulos et al., 2010). Caudate volume loss can also be detected in premanifesting HD and has been reported to correlate with the estimated time of disease onset based on the CAG expansion length (Aylward et al., 1996). Using VBM, it has been shown that striatal volumes in premanifesting HD correlate with protrusion of tongue force, tapping accuracy to a metronome, and errors in antisaccade production (Scahill et al., 2013). Precuneus atrophy was associated with impaired recognition of facial emotions in photographs. The availability of diffusion-weighted and tensor imaging has now become widespread, and this modality has proved to be very sensitive to the presence of structural damage. In symptomatic HD, changes in motor striatum water diffusivity have been reported to correlate with disease severity when rated with the Unified Huntington’s Disease Rating Scale (UHDRS) (Bohanna et al., 2011). In another series of early symptomatic HD cases (Delmaire et al., 2013), mean diffusivity in the anterior putamen and head of caudate nucleus correlated with impairments in self-paced finger tapping, impairment of sense of smell rated with the University of Pennsylvania Smell Identification Test (UPSIT), and performance on Trail Making Tests. Reductions in cortical fractional anisotropy and increases in cortical mean water diffusivity have also been linked to clinical deficits in early HD (Tabrizi et al., 2009). In one series (Delmaire et al., 2013), patients showed significant correlations between the following: (a) accuracy of self-paced tapping and mean diffusivity in the parietal and prefrontal areas; (b) impairment of the sense of smell rated with the UPSIT and water diffusivity in the parietal and median temporal lobes, cingulate, and insula and reductions in fractional anisotropy in the insula and the external capsule; (c) performance on the Trail Making Test part B (a measure of executive function) and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal, and postcentral areas; and (d) the levels of apathy and reduced fractional anisotropy in the white matter of the rectus gyrus.
uncertain. A second familial cause of generalized dystonia is DYT6 due to mutations in the THAP1 gene on chromosome 8p. THAP1 is a DNA binding transcription factor that regulates the promoter of TOR1A, and mutations of this gene result in phenotypes that overlap with the DYT1 phenotypes. DYT6 has a 60% penetrance and generally presents as an adult-onset craniocervical or focal dystonia but occasionally manifests in childhood as a generalized dystonia. Conventional T1- and T2-weighted MRIs show no significant abnormalities in the genetic dystonias though cases of acquired dystonia can show caudate, putamen, globus pallidus, and posterior thalamus signal changes (Bhatia & Marsden, 1994). This has led to the suggestion that torsion dystonia arises due to a reduced inhibitory output from the basal ganglia to ventral thalamus causing premotor areas to become inappropriately overactive. However, more recent DTI studies in the genetic dystonias have implicated a primary role for the cerebellum in this disorder. Tractography with DTI has demonstrated tract malformations in DYT1 and DYT6. The process takes a target nucleus as a seed and then probabilistically constructs white matter tracts connecting the seed to other structures from measures of the amplitude and directionality of water proton diffusivity at a voxel level. In the dystonia associated with DYT1 mutations, abnormal structural connectivities between the cerebellar nuclei, pons, and thalamus and between the striatum and premotor cortex have been demonstrated with tractography (see Figure 1) (Carbon & Eidelberg, 2009; Niethammer, Carbon, Argyelan, & Eidelberg, 2011). Nonmanifesting DYT1 carriers showed severe disruption of both cerebellar–pontine–thalamic and striato–sensorimotor cortex connections while manifesting carriers showed relatively preserved striatofrontal connections. These workers hypothesized that dystonia arises primarily from aberrant transmission in cerebellar–thalamic rather than basal ganglia projections and that the presence of striatofrontal connection disruption was protective, blocking dysfunctional effects arising from the altered cerebellar output (Niethammer et al., 2011). Deep brain stimulation of the internal pallidum may act to improve genetic dystonia by depressing basal ganglia output to the motor cortex and so inducing a blockade of the aberrant cerebellar–thalamic transmission.
MRI in Dystonia The most common familial form of generalized dystonia (DYT1) is an autosomal dominant disorder associated with a TOR1A gene mutation on chromosome 9q34. It has around a 30% penetrance and is generally early-onset, starting in the lower limb. The genetic mutation is a GAG deletion within the coding region of the gene responsible for torsin A, an ATPbinding chaperone protein whose exact function is still
Controls (n = 7)
DYT1 (n = 7)
Figure 1 Reduced cerebellar–thalamic and striatofrontal connections on tractography in DYT1 dystonia. Reproduced from Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., & Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia. Neurology, 72(24), 2097–2103.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
Functional Imaging Functional imaging provides a means of detecting and characterizing the regional changes in human brain metabolism and receptor binding associated with hyperkinetic movement disorders. In genetic choreas and dystonias, the major role of functional imaging is to throw light on the pathophysiology underlying involuntary movements and to detect evidence of disease activity in at-risk subjects. Functional imaging provides a sensitive means of detecting active subclinical disease and an objective biomarker of disease progression and in principle could determine whether this is influenced by novel neuroprotective strategies. There are four main approaches to functional imaging: positron emission tomography (PET) has high sensitivity, being able to detect femtomolar levels of positron-emitting radioisotopes at a spatial resolution of 2–3 mm in humans. It allows quantitative in vivo examination of alterations in regional cerebral blood flow (rCBF), glucose, and oxygen metabolism, enzyme activities, and brain surface receptor binding. Brain inflammation, evidenced as translocator protein (TSPO) expression by activated microglia, can be detected in patients with both neurodegenerative and inflammatory disorders. Single-photon emission computed tomography (SPECT) is less sensitive but more widely available than PET and can provide measures of rCBF and receptor binding. Magnetic resonance spectroscopy (MRS) has lower sensitivity and spatial resolution than radioisotope imaging approaches, detecting metabolite levels (N-acetylaspartate, lactate, phospholipids, and ATP) in the millimolar range at a 1 cm spatial resolution. Finally, using the blood oxygen level-dependent (BOLD) technique to detect local changes in venular oxygenation, MRI can detect activation-induced flow changes over a timescale of seconds when subjects perform tasks. Brain regions that are functionally interconnected show synchronization of slow oscillations in their venular oxygenation when BOLD sequences are run under resting conditions. This allows networks subserving attention, executive, and motor function to be delineated with resting fMRI and covariance analysis and their disruption by involuntary movement disorders to be demonstrated.
Functional Imaging of Choreas While the neurodegenerative disorders HD, HDL syndromes, NA, DRPLA, and BFC are all associated with chorea, it can also be a feature of inflammatory disorders such as the vasculitis SLE and poststreptococcal infection (Sydenham’s chorea). Chronic dopamine D2 receptor blockade by exposure to neuroleptics or vestibular sedatives can result in tardive chorea. Clinically manifesting HD patients show severely reduced levels of resting glucose and oxygen metabolism of their caudate and lentiform nuclei (Hayden et al., 1986; Kuhl et al., 1982; Leenders, Frackowiak, Quinn, & Marsden, 1986). Levels of resting putamen metabolism correlate with locomotor function while caudate metabolism correlates with performance on executive tests sensitive to frontal lobe function (Berent et al., 1988; Young et al., 1986). In early HD, cortical metabolism is preserved but as the disease progresses and dementia becomes
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prominent, it declines, the frontal cortex being particularly targeted (Kuwert, Lange, Langen, Herzog, Aulich, et al., 1990). Caudate hypometabolism, however, is not specific to HD, being seen in NA, DRPLA, and cases of BFC (Dubinsky, Hallett, Levey, & Di Chiro, 1989; Hosokawa et al., 1987; Kuwert, Lange, Langen, Herzog, Hefter, et al., 1990; Suchowersky et al., 1986). In contrast, striatal glucose metabolism is normal or elevated in inflammatory choreas (Guttman et al., 1987; Weindl et al., 1993) and also in tardive dyskinesia (Andersson et al., 1990; Pahl, Mazziotta, Bartzokis, Cummings, Altschuler, et al., 1987) discriminating these disorders from the degenerative choreas. Regional cerebral metabolism in HD has been studied with proton MRS. N-Acetylaspartate levels in the basal ganglia are reduced in manifesting patients, whereas lactate levels in the basal ganglia and cortex are elevated, suggesting that mitochondrial dysfunction is a component of this disorder (Jenkins, Koroshetz, Beal, & Rosen, 1993). Lactate levels have been reported to be normal in asymptomatic gene carriers, suggesting that the mitochondrial dysfunction seen in HD represents an associated secondary rather than a causative event. The medium spiny striatal neurons that degenerate in HD express surface dopamine D1, D2, opioid, cannabinoid CB1, and benzodiazepine receptors. PET and SPECT studies with benzamide- and spiperone-based tracers have reported that striatal D2 binding is reduced on average by 60% in manifesting HD gene carriers and by at least 30% at the onset of clinical symptoms (Antonini et al., 1996; Brucke et al., 1991; Turjanski, Weeks, Dolan, Harding, & Brooks, 1995). 11CSCH23390 PET studies in HD have demonstrated reduced D1 binding in both the striatum and temporal cortex (Karlsson et al., 1994). Turjanski et al. (1995) used 11C-SCH23390 and 11 C-raclopride PET to study both D1 binding and D2 binding in HD. They found a parallel reduction in striatal binding to these receptor subtypes irrespective of choreic or rigid phenotype, reductions in D1 and D2 binding both correlating with the severity of rigidity rather than chorea. Striatal opioid (Weeks et al., 1997), CB1 (Van Laere et al., 2010), and benzodiazepine (Holthoff et al., 1993) binding have also been shown to be reduced in clinically affected HD patients. Reductions are smaller, however, compared to the loss of dopamine receptors. Reduced striatal dopamine receptor binding can also be seen in other degenerative choreas and a mean 70% reduction of striatal 11C-raclopride binding has been reported in NA (Brooks et al., 1991). In contrast, normal striatal D2 binding has been reported in SLE chorea (Turjanski et al., 1995) and tardive dyskinesia (Andersson et al., 1990; Blin et al., 1989 Nov). This finding argues against the hypothesis that tardive dyskinesia (TD) results from striatal D2 receptor supersensitivity following prolonged exposure to neuroleptics. Postmortem studies have reported downstream reductions in pallidal and subthalamic gamma aminobutyric acid (GABA) levels that may act to disinhibit basal ganglia output to the cortex (Andersson et al., 1989). As manifesting HD patients show at least a 30% loss of striatal dopamine receptor binding and glucose metabolism at symptom onset, 11C-SCH23390, 11C-raclopride, and 18 FDG (2-fluoro-2-deoxyglucose) PET should all be capable
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INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
of detecting subclinical dysfunction in premanifesting HD gene carriers. A significant parallel loss of striatal D1 and D2 binding in four of eight premanifesting HD gene carriers has been reported (Weeks, Piccini, Harding, & Brooks, 1996), while reduced caudate glucose metabolism was noted in 9 out of 12 and 3 out of 8 asymptomatic adult HD gene carriers in two other series (Grafton et al., 1990; Hayden, Hewitt, Martin, Clark, & Amman, 1987). Functional imaging has been used to determine the rate of progression of HD. FDG PET has shown a 3.1% annual decline in caudate glucose metabolism in manifesting HD patients (Grafton et al., 1992) while 11C-raclopride PET revealed an annual 6% change in striatal D2 binding (Antonini, Leenders, & Eidelberg, 1998 Feb). An annual 3–4% loss of striatal D1 and D2 binding was detected in manifesting HD gene carriers and a 6% loss in those 50% of adult premanifesting HD gene carriers where disease was subclinically active (Andrews et al., 1999). 11 C-raclopride PET has also detected early loss of frontal D2 binding in HD (Pavese et al., 2002). These findings all suggest that functional imaging provides an objective means of following HD progression and could be a marker of efficacy when testing putative neuroprotective or restorative interventions.
Imaging Inflammation in HD The microglia constitute 10–20% of white cells in the brain and form its natural defense mechanism. They are normally in a resting state, but local injury causes them to activate and swell, expressing human leukocyte antigen (HLA) antigens on the cell surface and releasing cytokines and growth factors. The mitochondria of activated but not resting microglia express the TSPO, which is a steroid and anion transporter and helps regulate membrane potential. The TSPO was previously known as the peripheral benzodiazepine receptor although it does not possess classical receptor properties. 11C-PK11195 is an isoquinoline derivative that binds selectively to an isoquinoline site on the TSPO and so provides an in vivo PET marker of the level and spatial extent of microglial activation. Postmortem studies of HD brains have shown a significant accumulation of activated microglia in the basal ganglia and the frontal cortex (Sapp et al., 2001). Manifesting HD patients show increased striatal 11C-PK11195 binding, the levels of which correlate with clinical disease severity scored with the UHDRS (Pavese et al., 2005). Levels of striatal microglial activation also correlate with striatal reductions in 11C-raclopride binding (see Figure 2) and with the size of the patients’ CAG triplet expansion suggesting that microglial activation plays a role in driving the neurodegenerative process. Increased striatal 11 C-PK11195 binding can be detected with 11C-PK11195 PET in a majority of adult premanifesting HD gene carriers and also cortical binding if statistical parametric mapping is employed (Tai et al., 2007). This suggests that microglial activation is an early event in HD and its suppression could be therapeutically beneficial.
Functional Imaging of Dystonia FDG PET has shown that DYT1 carriers have regional brain levels of resting glucose metabolism in the normal range.
Normal
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Microglial activation 11C-PK11195
D2 receptors 11C-raclopride
Figure 2 11C-PK11195 and 11C-raclopride PET scans of a healthy subject and HD gene carrier. Significantly raised microglial activation is evident in the frontal cortex and striata of the HD patient along with reductions in striatal D2 binding. Courtesy of Dr. Thomasin Andrews.
However, covariance analysis between regional and voxel levels of rCMRGlc reveals an abnormal resting metabolic profile where posterior lentiform nucleus, thalamic, and supplementary motor area glucose metabolism is relatively raised (Carbon & Eidelberg, 2009). This torsion dystonia-related profile (TDRP) is seen whether DYT1 gene carriers are manifesting or premanifesting. A PET study on blepharospasm patients performed while they were asleep also showed this abnormal profile of resting glucose metabolism confirming that it is not simply related to involuntary movements (Hutchinson et al., 2000). Manifesting DYT6 dystonias show a similar TDRP to DYT1 cases (Carbon et al., 2004). These findings suggest that overactivity of a common network involving the basal ganglia and frontal cortex may underlie all the genetic dystonias. Manifesting DYT1 carriers were shown to have relatively higher levels of metabolism in the pre-supplementary motor area (pre-SMA) and parietal association cortices and lower levels in the inferior cerebellum, brain stem, and ventral thalamus compared with nonmanifesting carriers (Carbon, Argyelan, & Eidelberg, 2010). This finding would fit with the view that abnormal sensorimotor integration underlies these involuntary movements. 18 F-dopa PET and 123I-beta-CIT SPECT studies have shown normal striatal dopamine terminal function in the majority of idiopathic dystonia cases (Naumann et al., 1998; Playford, Fletcher, Sawle, Marsden, & Brooks, 1993). In contrast, PET and SPECT have shown that striatal D2 binding is significantly reduced (Naumann et al., 1998; Perlmutter et al., 1997). In one 11 C-raclopride PET series, DYT1 carriers had a mean 15% and DYT6 carriers a mean 38% reduction in striatal D2 binding regardless of clinical penetrance (Figure 3) (Carbon et al., 2009). Reductions in striatal D2 expression could result in decreased activity of the indirect striatopallidal pathway, which normally acts to inhibit unwanted movement or actions. Recently, it has been reported that uptake of 11Cflumazenil, a marker of benzodiazepine receptor binding on the GABAA complex, is reduced in motor and premotor areas in a group of DYT1 and sporadic dystonias (Garibotto et al.,
Putamen
R
t 4.8 4.4
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INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
3 2.5 2 1.5 1 0.5 0 C
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0.6 Thalamus
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0.5 0.4 0.3 0.2 0.1 0 C
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Figure 3 Loss of striatal and thalamic dopamine D2 binding in DYT1 dystonia. Reproduced from Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., & Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia. Neurology, 72(24), 2097–2103.
2011). Such a deficit in GABAergic function could result in a failure of normal cortical inhibitory circuits.
Motor Activation in Dystonia Cerebral activation studies in idiopathic torsion dystonia have suggested an imbalance between sensorimotor and premotor cortex functions. If dystonia patients perform paced joystick movements with their right hands in freely selected directions, they show significantly increased levels of contralateral putamen, rostral supplementary motor area, lateral premotor cortex, and dorsolateral prefrontal area activation (CeballosBaumann et al., 1995). In contrast, activation of contralateral sensorimotor cortex and caudal SMA is impaired; these are the motor cortical areas that send direct pyramidal tract projections to the spinal cord. Attenuation of sensorimotor cortex and caudal SMA activation in generalized and focal dystonia during vibrotactile stimulation have also been reported (Tempel & Perlmutter, 1990, 1993). Abnormal overactivation of premotor and parietal areas and the cerebellum has been demonstrated during sequence learning in nonmanifesting DYT1 carriers despite their impaired performance on the task (Carbon et al., 2008).
Dopamine-Responsive Dystonia and Dystonia–Parkinsonism Dominantly inherited dopamine-responsive dystonia (DRD) is related to a mutation in the DYT5 gene coding for GTP cyclohydrolase 1. This enzyme constitutes part of the tetrahydrobiopterin synthetic pathway, the cofactor for tyrosine hydroxylase. Patients are unable to manufacture levodopa, and hence dopamine, from endogenous tyrosine but can still convert exogenous
levodopa to dopamine. DRD cases generally present in childhood with diurnally fluctuating dystonia and later develop background parkinsonism. Occasionally, the condition presents as pure parkinsonism in adulthood. 18F-dopa PET and 123I-betaCIT SPECT findings are normal in DRD patients (Naumann et al., 1997; Sawle et al., 1991), distinguishing this condition from early-onset dystonia–parkinsonism where severely reduced putamen 18F-dopa and 123I-beta-CIT uptake is seen (Turjanski et al., 1993).
Conclusions Structural and functional imaging can sensitively detect evidence of disease activity in HD gene carriers a decade before symptoms manifest. Both modalities could be used to track disease progression and to determine the efficacy of potential neuroprotective and restorative interventions. The inflammatory- and drug-related choreas can be discriminated from degenerative choreas by their preservation of striatal metabolism and receptor binding. DTI detects abnormal cerebellar–thalamic and premotor– striatal connectivity in the genetic dystonias, the first causing and the second possibly acting to suppress disease manifestation. PET reveals a common abnormal resting profile of increased lentiform nucleus and premotor glucose metabolism underlying the genetic dystonias. Reduced striatal D2 binding and cortical benzodiazepine receptor binding are also seen, which could contribute to the premotor cortical disinhibition associated with these involuntary movements.
References Andersson, U., Eckernas, S. A., Hartvig, P., Ulin, J., Langstrom, B., & Haggstrom, J. E. (1990). Striatal binding of 11c-NMSP studied with positron emission tomography
756
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in patients with persistent tardive dyskinesia: No evidence for altered dopamine receptor binding. Journal of Neural Transmission, 79, 215–226. Andersson, U., Haggstrom, J.-E., Levin, E. D., Bondesson, U., Valverius, M., & Gunne, L. M. (1989). Reduced glutamate decarboxylase activity in the subthalamic nucleus of patients with tardive dyskinesia. Movement Disorders, 4, 37–46. Andrews, T. C., Weeks, R. A., Turjanski, N., Gunn, R. N., Watkins, L. H. A., Sahakian, B., et al. (1999). Huntington’s disease progression pet and clinical observations. Brain, 122, 2353–2363. Antonini, A., Leenders, K. L., & Eidelberg, D. (1998). [C-11]Raclopride-pet studies of the Huntington’s disease rate of progression: Relevance of the trinucleotide repeat length. Annals of Neurology, 43(2), 253–255. Antonini, A., Leenders, K. L., Spiegel, R., Meier, D., Vontobel, P., Weigell Weber, M., et al. (1996). Striatal glucose metabolism and dopamine D-2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain, 119, 2085–2095. Aylward, E. H., Anderson, N. B., Bylsma, F. W., Wagster, M. V., Barta, P. E., Sherr, M., et al. (1998). Frontal lobe volume in patients with Huntington’s disease. Neurology, 50(1), 252–258. Aylward, E. H., Codori, A. M., Barta, P. E., Pearlson, G. D., Harris, G. J., & Brandt, J. (1996). Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Archives of Neurology, 53(12), 1293–1296. Aylward, E. H., Codori, A. M., Rosenblatt, A., Sherr, M., Brandt, J., Stine, O. C., et al. (2000). Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Movement Disorders, 15(3), 552–560. Berent, S., Giordani, B., Lehtinen, S., Markel, D., Penney, J. B., Buchtel, H. A., et al. (1988). Positron emission tomographic scan investigations of Huntington’s disease – cerebral metabolic correlates of cognitive function. Annals of Neurology, 23, 541–546. Bhatia, K. P., & Marsden, C. D. (1994). The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain, 117, 859–876. Blin, J., Baron, J. C., Cambon, H., Bonnet, A. M., Dubois, B., Loc’h, C., et al. (1989 Nov). Striatal dopamine D2 receptors in tardive dyskinesia: Pet study. Journal of Neurology, Neurosurgery, and Psychiatry, 52(11), 1248–1252. Bohanna, I., Georgiou-Karistianis, N., Sritharan, A., Asadi, H., Johnston, L., Churchyard, A., et al. (2011). Diffusion tensor imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits. Brain Imaging and Behavior, 5(3), 171–180. Brooks, D. J., Ibanez, V., Playford, E. D., Sawle, G. V., Leigh, P. N., Kocen, R. S., et al. (1991). Presynaptic and postsynaptic striatal dopaminergic function in neuroacanthocytosis: A positron emission tomographic study. Annals of Neurology, 30, 166–171. Brucke, T., Podreka, I., Wenger, S., Angelberger, P., Muller, C., Walter, H., et al. (1991). Dopamine receptor imaging with SPECT: A diagnostic tool in extrapyramidal disorders and in vivo assay for the measurement of receptor blockade by neuroleptic treatment. Journal of Cerebral Blood Flow and Metabolism, 11(Suppl. 2), S877. Carbon, M., Argyelan, M., & Eidelberg, D. (2010). Functional imaging in hereditary dystonia. European Journal of Neurology, 17(Suppl. 1), 58–64. Carbon, M., & Eidelberg, D. (2009). Abnormal structure-function relationships in hereditary dystonia. Neuroscience, 164(1), 220–229. Carbon, M., Ghilardi, M. F., Argyelan, M., Dhawan, V., Bressman, S. B., & Eidelberg, D. (2008). Increased cerebellar activation during sequence learning in DYT1 carriers: An equiperformance study. Brain, 131(Pt 1), 146–154. Carbon, M., Niethammer, M., Peng, S., Raymond, D., Dhawan, V., Chaly, T., et al. (2009). Abnormal striatal and thalamic dopamine neurotransmission: Genotyperelated features of dystonia. Neurology, 72(24), 2097–2103. Carbon, M., Su, S., Dhawan, V., Raymond, D., Bressman, S., & Eidelberg, D. (2004). Regional metabolism in primary torsion dystonia: Effects of penetrance and genotype. Neurology, 62(8), 1384–1390. Ceballos-Baumann, A. O., Passingham, R. E., Warner, T., Playford, E. D., Marsden, C. D., & Brooks, D. J. (1995). Overactivity of rostral and underactivity of caudal frontal areas in idiopathic torsion dystonia: A Pet activation study. Annals of Neurology, 37, 363–372. Delmaire, C., Dumas, E. M., Sharman, M. A., van den Bogaard, S. J., Valabregue, R., Jauffret, C., et al. (2013). The structural correlates of functional deficits in early Huntington’s disease. Human Brain Mapping, 34(9), 2141–2153. Dubinsky, R. M., Hallett, M., Levey, R., & Di Chiro, G. (1989). Regional brain glucose metabolism in neuroacanthocytosis. Neurology, 39, 1253–1255. Garibotto, V., Romito, L. M., Elia, A. E., Soliveri, P., Panzacchi, A., Carpinelli, A., et al. (2011). In vivo evidence for GABA(a) receptor changes in the sensorimotor system in primary dystonia. Movement Disorders, 26(5), 852–857. Georgiou-Karistianis, N., Scahill, R., Tabrizi, S. J., Squitieri, F., & Aylward, E. (2013). Structural MRI in Huntington’s disease and recommendations for its potential use in clinical trials. Neuroscience and Biobehavioral Reviews, 37(3), 480–490.
Grafton, S. T., Mazziotta, J. C., Pahl, J. J., St George Hyslop, P., Haines, J. L., Gusella, J., et al. (1992). Serial changes of glucose cerebral metabolism and caudate size in persons at risk for Huntington’s disease. Archives of Neurology, 49, 1161–1167. Grafton, S. T., Mazziotta, J. C., Pahl, J. J., St. George-Hyslop, P., Haines, J. L., Gusella, J., et al. (1990). A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington’s disease. Annals of Neurology, 28, 614–621. Guttman, M., Lang, A. E., Garnett, E. S., Nahmias, C., Firnau, G., Tyndal, F. J., et al. (1987). Regional cerebral glucose metabolism in SLE chorea: Further evidence that striatal hypometabolism is not a correlate of chorea. Movement Disorders, 2, 201–210. Harrington, D. L., Liu, D., Smith, M. M., Mills, J. A., Long, J. D., Aylward, E. H., et al. (2014). Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain and Behavior, 4(1), 29–40. Hayden, M. R., Hewitt, J., Martin, W. R. W., Clark, C., & Amman, A. (1987). Studies in persons at risk for Huntington’s disease. The New England Journal of Medicine, 317, 382–383. Hayden, M. R., Martin, W. R. W., Stoessl, A. J., Clark, C., Hollenberg, S., Adam, M. J., et al. (1986). Positron emission tomography in the early diagnosis of Huntington’s disease. Neurology, 36, 888–894. Hayflick, S. J., Hartman, M., Coryell, J., Gitschier, J., & Rowley, H. (2006). Brain MRI in neurodegeneration with brain iron accumulation with and without Pank2 mutations. AJNR - American Journal of Neuroradiology, 27(6), 1230–1233. Holthoff, V. A., Koeppe, R. A., Frey, K. A., Penney, J. B., Markel, D. S., Kuhl, D. E., et al. (1993). Positron emission tomography measures of benzodiazepine receptors in Huntington’s disease. Annals of Neurology, 34, 76–81. Hosokawa, S., Ichiya, Y., Kuwabara, Y., Ayabe, Z., Mitsuo, K., Goto, I., et al. (1987). Positron emission tomography in cases of chorea with different underlying diseases. Journal of Neurology, Neurosurgery, and Psychiatry, 50, 1284–1287. Hutchinson, M., Nakamura, T., Moeller, J. R., Antonini, A., Belakhlef, A., Dhawan, V., et al. (2000). The metabolic topography of essential blepharospasm: A focal dystonia with general implications. Neurology, 55(5), 673–677. Jenkins, B. G., Koroshetz, W. J., Beal, M. F., & Rosen, B. R. (1993). Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localised 1 h NMR spectroscopy. Neurology, 43, 2689–2695. Karlsson, P., Lundin, A., Anvret, M., Suhara, T., Halldin, C., & Farde, L. (1994). Dopamine D1 receptor number – A sensitive PET marker for early brain degeneration in Huntington’s disease. European Archives of Psychiatry and Neurological Sciences, 243, 249–255. Kuhl, D. E., Phelps, M. E., Markham, C. H., Metter, E. J., Riege, W. H., & Winter, E. J. (1982). Cerebral metabolism and atrophy in Huntington’s disease determined by 18 FDG and computed tomographic scans. Annals of Neurology, 12, 425–434. Kuwert, T., Lange, H. W., Langen, K. J., Herzog, H., Aulich, A., & Feinendegen, L. E. (1990). Cortical and subcortical glucose consumption measured by PET in patients with Huntington’s disease. Brain, 113, 1405–1423. Kuwert, T., Lange, H. W., Langen, K. J., Herzog, H., Hefter, H., Aulich, A., et al. (1990). Normal striatal glucose consumption in two patients with benign hereditary chorea as measured by positron emission tomography. Journal of Neurology, 237, 80–84. Leenders, K. L., Frackowiak, R. S.J, Quinn, N., & Marsden, C. D. (1986). Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Movement Disorders, 1, 69–77. Marsden, C. D., Obeso, J. A., Zarranz, J. J., & Lang, A. E. (1985). The anatomical basis of symptomatic hemidystonia. Brain, 108, 463–483. McNeill, A., Gorman, G., Khan, A., Horvath, R., Blamire, A. M., & Chinnery, P. F. (2012). Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate. AJNR - American Journal of Neuroradiology, 33(9), 1810–1813. Naumann, M., Pirker, W., Reiners, K., Lange, K., Becker, G., & Brucke, T. (1997). [123i] Beta-Cit single-photon emission tomography in dopa-responsive dystonia. Movement Disorders, 12(3), 448–451. Naumann, M., Pirker, W., Reiners, K., Lange, K. W., Becker, G., & Brucke, T. (1998). Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: A SPECT study using [123i]epidepride and [123i]BCIT. Movement Disorders, 13, 319–323. Niethammer, M., Carbon, M., Argyelan, M., & Eidelberg, D. (2011). Hereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging. Neurobiology of Disease, 42(2), 202–209. Nopoulos, P. C., Aylward, E. H., Ross, C. A., Johnson, H. J., Magnotta, V. A., Juhl, A. R., et al. (2010). Cerebral cortex structure in prodromal Huntington disease. Neurobiology of Disease, 40(3), 544–554. Pahl, J. J., Mazziotta, J. C., Bartzokis, G., Cummings, J., Altschuler, L., Mintz, J., et al. (1995). Positron-emission tomography in tardive dyskinesia. The Journal of Neuropsychiatry and Clinical Neurosciences, 7, 457–465.
INTRODUCTION TO CLINICAL BRAIN MAPPING | Chorea and Other Hyperkinetic Disorders
Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., et al. (2005). Activated microglia accompany neuronal dysfunction in Huntington’s disease. An C-11-raclopride and C-11-(R)-Pk11195 PET study. Neurology, 64(6), A91. Pavese, N., Rosser, A. E., Brooks, D. J., Barker, R. A., Dunnett, S. B., & Piccini, P. (2002). Cortical dopamine D2 receptor dysfunction in Huntington’s disease. Movement Disorders, 17, P1050. Perlmutter, J. S., Stambuk, M. K., Markham, J., Black, K. J., McGee-Minnich, L., Jankovic, J., et al. (1997). Decreased [F-18] spiperone binding in putamen in idiopathic focal dystonia. Journal of Neuroscience, 17, 843–850. Playford, E. D., Fletcher, N. A., Sawle, G. V., Marsden, C. D., & Brooks, D. J. (1993). Integrity of the nigro-striatal dopaminergic system in familial dystonia: An 18f-dopa PET study. Brain, 116, 1191–1199. Ruocco, H. H., Lopes-Cendes, I., Li, L. M., Santos-Silva, M., & Cendes, F. (2006). Striatal and extrastriatal atrophy in Huntington’s disease and its relationship with length of the CAG repeat. Brazilian Journal of Medical and Biological Research, 39(8), 1129–1136. Sapp, E., Kegel, K. B., Aronin, N., Hashikawa, T., Uchiyama, Y., Tohyama, K., et al. (2001). Early and progressive accumulation of reactive microglia in the Huntington disease brain. Journal of Neuropathology and Experimental Neurology, 60(2), 161–172. Sawle, G. V., Leenders, K. L., Brooks, D. J., Harwood, G., Lees, A. J., Frackowiak, R. S. J., et al. (1991). Dopa-responsive dystonia: [18f]Dopa positron emission tomography. Annals of Neurology, 30, 24–30. Scahill, R. I., Hobbs, N. Z., Say, M. J., Bechtel, N., Henley, S. M., Hyare, H., et al. (2013). Clinical impairment in premanifest and early Huntington’s disease is associated with regionally specific atrophy. Human Brain Mapping, 34(3), 519–529. Schipper, H. M. (2012). Neurodegeneration with brain iron accumulation – clinical syndromes and neuroimaging. Biochimica et Biophysica Acta, 1822(3), 350–360. Starosta-Rubinstein, S., Young, A. B., Kluin, K., Hill, G., Aisen, A. M., Gabrielsen, T., et al. (1987). Clinical assessment of 31 patients with Wilson’s disease: Correlations with structural changes on magnetic resonance imaging. Archives of Neurology, 44, 365–370. Suchowersky, O., Hayden, M. R., Martin, W. R. W., Stoessl, A. J., Hildebrand, A. M., & Pate, B. D. (1986). Cerebral metabolism of glucose in benign hereditary chorea. Movement Disorders, 1, 33–45. Tabrizi, S. J., Langbehn, D. R., Leavitt, B. R., Roos, R. A., Durr, A., Craufurd, D., et al. (2009). Biological and clinical manifestations of Huntington’s disease in the
757
longitudinal track-HD study: Cross-sectional analysis of baseline data. Lancet Neurology, 8(9), 791–801. Tai, Y. F., Pavese, N., Gerhard, A., Tabrizi, S. J., Barker, R. A., Brooks, D. J., et al. (2007). Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain, 130, 1759–1766. Tempel, L. W., & Perlmutter, J. S. (1990). Abnormal vibration-induced cerebral blood flow responses in idiopathic dystonia. Brain, 113, 691–707. Tempel, L. W., & Perlmutter, J. S. (1993). Abnormal cortical responses in patients with Writer’s cramp. Neurology, 43, 2252–2257. Turjanski, N., Bhatia, K., Burn, D. J., Sawle, G. V., Marsden, C. D., & Brooks, D. J. (1993). Comparison of striatal 18f-Dopa uptake in adult-onset dystoniaparkinsonism, Parkinson’s disease, and dopa-responsive dystonia. Neurology, 43, 1563–1568. Turjanski, N., Weeks, R., Dolan, R., Harding, A. E., & Brooks, D. J. (1995). Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas: A PET study. Brain, 118, 689–696. Van Laere, K., Casteels, C., Dhollander, I., Goffin, K., Grachev, I., Bormans, G., et al. (2010). Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine, 51(9), 1413–1417. Weeks, R. A., Cunningham, V. J., Piccini, P., Waters, S., Harding, A. E., & Brooks, D. J. (1997). 11c-Diprenorphine binding in Huntington’s disease: A comparison of region of interest analysis and statistical parametric mapping. Journal of Cerebral Blood Flow & Metabolism, 17, 943–949. Weeks, R. A., Piccini, P., Harding, A. E., & Brooks, D. J. (1996). Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington’s disease. Annals of Neurology, 40, 49–54. Weindl, A., Kuwert, T., Leenders, K. L., Poremba, M., Voneinsiedel, H. G., Antonini, A., et al. (1993). Increased striatal glucose consumption in Sydenham chorea. Movement Disorders, 8, 437–444. Wild, E. J., Mudanohwo, E. E., Sweeney, M. G., Schneider, S. A., Beck, J., Bhatia, K. P., et al. (2008). Huntington’s disease phenocopies are clinically and genetically heterogeneous. Movement Disorders, 23(5), 716–720. Young, A. B., Penney, J. B., Starosta-Rubinstein, S., Markel, D. S., Berent, S., Giordani, B., et al. (1986). PET scan investigations of Huntington’s disease: Cerebral metabolic correlates of neurological features and functional decline. Annals of Neurology, 20, 296–303.