CHAPTER 6 Movement Disorders: Structural and Functional Imaging 45 (a) (b) Fig. 6.3 Transcranial sonography showing hyperechogenicity from the lateral midbrain (subst antia nigra) in PD. (Picture from Berg et al. 2001) Parkinson \200\231s disease Th e presynaptic dopaminergic system Dopamine terminal function in PD can be examined in vivo in three main ways: structural connectivity between the cerebellar nuclei and the thala- mus and between fronta l cortex and striatum can be demonstrated with tractography, although conventional MRI appe ars normal (14). Th ese fi ndings all support idiopathic and genetic dystonias arising from an abnormal structural development of subcortical \200\223 cortical connections. terminal dopa decarboxylase activity can be measured with 18 F-dopa positron emission tomog raphy (PET); \227\206 Huntington \200\231s disease Huntington \200\231s disease (HD) is an autosomal dominantly t rans- mitted disorder associated with an excess of CAG triplet repeats (>38) in the hunting tin ( HTT ) gene on chromosome 4. The function of this gene is still uncertain, but the pat hology of HD targets medium spiny projection neurons in the striatum, causing intranuclear and cytoplasmic inclusions to form. While altered striatal T 2 -weighted MRI signal and cau date atrophy are only visually evident in cases of established HD (15), MR volumetry reveal s subclinical caudate and putamen atrophy in pre-manifest gene carriers close to predicted symptom onset (16). Striatal atrophy becomes more marked as they become symptomatic and dev elop motor signs. Aylward and colleagues (17) were able to predict time of conversion from preclinical to clinical HD by measuring caudate volumes. These workers sug- gested that cau date volume may be a useful outcome measure for assessing treatment effectiveness in both p re-manifest and symptomatic subjects. the availability of dopamine transporters (DATs) can be assessed with 11 C-methylphenidate (MP) PET or tropane-based PET and single photon emission computed tomography (SPECT) mark- ers such as 11 C-2- -carbomethoxy-3- -(4-fl uorophenyl)tropane ( 11 C-CFT), 18 F-FP-C IT, 123 I-altropane, 123 I- -CIT, and 123 I-FP- CIT; \227\206 vesicle monoamine transporter density (VMAT2) can be studied with 11 C- or 18 F-dihydrotetr abenazine (DTBZ) PET (Fig. 6.4) (18). \227\206 In PD patients with early stage 1 disease aff ecting only one side bilaterally reduced puta men tracer uptake can be seen, activity being most depressed in the putamen contralateral t o the clinic- ally aff ected limbs. Head-of-caudate dopamine terminal function remains rela tively preserved until later in the condition. Onset of symptoms has been estimated to occu r aft er a 30 \200\22350% loss of putamen dopamine terminal function (19). Unlike nigral hy per- echogenicity, reductions in putamen dopamine terminal func- tion correlate well with s everity of limb rigidity and bradykinesia although, interestingly, they correlate poorly wi th severity of tremor (20). Functional imaging Th e changes in regional cerebral function that characterize dif- ferent movement disorders can be examined in two main ways: fi rst, focal changes in resting leve ls of regional cerebral metabo- lism, blood fl ow, and neuroreceptor availability can be me as- ured. Secondly, abnormal patterns of regional brain activation, evidenced as changes in blood fl ow or levels of neurotransmit- ter release, can be detected when patients with mo vement disor- ders perform motor and cognitive tasks or are exposed to drug challenges. PET and SPECT can diff erentiate clinically probable PD from normal subjects or benign esse ntial and dystonic tremor patients with a sensitivity and specifi city of around 90% (21). An abnor- mal PET or SPECT scan provides support for a diagnosis of a dopamine-defi cient p arkinsonian syndrome and a rationale for treating with dopaminergic agents, while a normal scan eff ectively excludes this diagnosis. Several studies have examined the utility of using DAT imaging to determine whether \200 \230gray \200\231 parkinsonian cases are associated with Oxford Textbook of Movement Disorders 46 18F-DTBZ VMAT2 11C-DTBZ VMAT2 18F-dopa DDC 123I-altropane DAT 123I-io \202upane DAT Healthy PD Fig. 6.4 SPECT and PET images of dopamine terminal function in normal subjects and early PD patients. striatal dopamine defi ciency. In the Query PD study the standard of truth (SOT) was the cl inical impression of two movement disorder experts aft er 6 months of clinical follow-up (2 2). While referring cli- nicians showed 92% sensitivity for diagnosing dopamine-defi cient parkinsonism, their baseline clinical specifi city was poor (30%) compared with the SOT, wh ile baseline imaging specifi city with 123 I- -CIT SPECT was 100%. Th ese fi ndings sugg est that clinicians tend to overdiagnose PD when uncertain. Th e Clinically Uncertain Parki nsonian Syndromes (CUPS) trial was designed to establish whether knowledge of baseline stri atal DAT binding infl uenced the diagnosis and subsequent management of patients with uncer tain PD (23). When FP-CIT SPECT fi ndings were revealed to clini- cians, the diagnosis of d opamine-defi cient parkinsonian syndrome was revised in 52% of the 118 cases and the manage ment strategy changed in 72% of cases. A two-year follow-up found that 90% of subjects stil l retained the diagnosis assigned aft er baseline FP-CIT SPECT fi ndings were released (24) . Th e CUPS study supports the view that including a measure of striatal dopaminergic funct ion in the work-up of uncertain parkinsonian cases infl uences their sub- sequent managemen t. diagnostic doubts led to DAT imaging with FP-CIT SPECT. Th is was negative, and subsequent withdrawal of antiparkinsonian ther- apy was achieved without clinical deterioration, sugge sting that dopaminergic imaging can be valuable where inappropriate use of antiparkinsonian medication is suspected. Postsynaptic dopaminergic receptor binding Th e striatum contains primarily dopamine D1 and D2 receptor subtypes which both play a role in modulating locomotor func- tion. 123 I-iodo benzamine ( 123 I-IBZM) SPECT studies have reported normal levels of striatal D2 binding in untreated PD (Fig. 6.5) while 11 C-raclopride PET detects a 10 \200\22320% increase in put amen D2 availability (18). As 11 C-raclopride competes with endogenous dopamine for D2 bind ing, this raised receptor availability probably refl ects dopamine depletion rather than an adaptive rise in recep- tor numbers. In chronically levodopa-exposed PD cases levels of pu tamen D2 binding normalize as synaptic levels of dopamine are restored. Measuring striatal dopamine As 11 C-raclopride competes with synaptic dopamine to bind to D 2 receptors its uptake is sensitive to changes in synaptic levels of striatal dopamine. PET can be used to detect changes in dopamine induced by drugs or behavior. Microdialysis stud ies in animals suggest that a 10% reduction in striatal 11 C-raclopride binding refl ects a fi vefold increase in synaptic dopamine levels (28). When Th ere was no non-imaged control group as a comparator in the CUPS study, so the prevalence of change in management plan with- out SPECT was not determined. Th e PDT409 study, which had a similar design but included a control arm, has recently reported (25). Th ere were ar ound 130 possible PD cases in each arm, and patients were assessed at baseline and assigned a diagnosis and management plan. Twelve weeks aft er FP-CIT SPECT or no imag- ing they wer e re-assessed and their diagnosis and management reviewed. Forty-four per cent who had SPEC T versus 12% who were not imaged had a change in their diagnosis aft er 12 weeks of follow- up, while 49% in the imaging arm versus 31% in the non-imaged arm had a change of managemen t plan. A common cause of confusion with PD is adult-onset dystonic tremor which can present as an asymmetric resting arm tremor with impaired arm swing and cogwheel rigidity, but without ev idence of true akinesia (26). In these cases functional imaging should be considered to avo id inappropriate medication with dopaminergic agents. Other causes of confusion include dru g-associated and psy- chogenic parkinsonism. Marshall and co-workers (27) presented eleven patients who initially fulfi lled diagnostic criteria for PD and were treated with dopamine rgic agents, but in whom emerging Fig. 6.5 123 I-IBZM SPECT images of dopamine D2 receptor binding in a normal subject and in PD and MSA cases. Striatal D2 binding is reduced in the MSA case. (Picture courtesy of Dr G. Wenning) CHAPTER 6 Movement Disorders: Structural and Functional Imaging 47 Modifying progression of PD As functional imaging can objectively follow loss of dopamine t er- minal function in PD, it provides a potential means of monitoring the effi cacy of puta tive neuroprotective agents. In the REAL PET ( 18 F-dopa) and CALM PD ( -CIT SPECT) tria ls (38, 39), early PD patients were shown to lose dopamine terminal function a third more s lowly if treated with a dopamine agonist as opposed to levodopa. Th e incidence of complica tions was also signifi cantly reduced in the agonist cohorts, but improvements in disabilit y were greater in the levodopa cohorts. Th e interpretation of these data has remained cont roversial because of the discordance between imag- ing and clinical outcomes. It is possibl e that levodopa acts directly to downregulate -CIT and 18 F-dopa uptake, thus confoundin g the utility of these imaging biomarkers for assessing neuroprotective effi cacy in the pr esence of dopaminergic agents. PET and SPECT have also been used as imaging biomarkers to e xamine the pos- sible neuroprotective effi cacy of riluzole and paliroden ( 18 F-dopa PET), TCH346, and CEP1347 ( -CIT SPECT) \200\224these trials were all negative and CEP1347 tr eatment was shown to depress striatal -CIT uptake (40). PD patients take oral levodopa, transient rises in synaptic dopamine result. 11 C-racloprid e PET has shown that improvement in disabil- ity aft er levodopa correlates with the estima ted rises in putamen dopamine (29). Some PD patients compulsively take far larger doses of levodopa than are clinically required \200\224this has been termed the dopamine dysregulati on syndrome (DDS). Compared with PD patients who are not compulsively taking excess medicat ion, DDS patients show enhanced levodopa-induced dopamine release in the ventral striatum ( 30). PD cases who develop impulse control disor- ders, such as compulsive gambling, when ad ministered dopamine agonist therapy also release higher levels of ventral striatal dopamine when exposed to the relevant stimuli such as games of chance (31). Detection of preclinical PD It has been estimated from post-mortem studies that, for every patient who develops clinical PD, there are ten subclinical cases with incidental brainstem Lewy body disease in the commu- nity. Th e greatest risk factors for PD are age and a fami ly his- tory. Late-onset idiopathic hyposmia and REM sleep behavior disorder (RBD) are also associated with later onset of Lewy body disorders. 18 F-dopa PET has detected subclinical ly reduced dopaminergic function in asymptomatic identical twins and relatives of idiopathi c PD cases, and in parkin and LRRK2 gene carriers (18). Reduced striatal DAT binding can be detected in around 10% of late-onset hyposmic subjects (32) and a majority of patients wit h idiopathic RBD (33). Two major double-blind controlled trials on the effi cacy of implantation of human fetal ce lls in PD have been sponsored by the National Institutes of Health (NIH) in the USA (41, 42 ). Despite both histological and 18 F-dopa PET evidence of graft function, nei- ther of the se controlled trials demonstrated clinical effi cacy accord- ing to their primary endpoints . However, there were indications that younger, more severely aff ected patients benefi ted from intra- striatal implantation of human fetal dopamine cells. An issue raised by both t hese trials was the occurrence of problematic \200\230off \200\231 period dyskinesias in many implanted patients. Levodopa-induced dyskinesias PD patients with early disease and sustained therapeutic respo nses to levodopa show a reduction in striatal 11 C-raclopride binding aft er oral levodopa that is maintained for several hours, compatible with a sustained increase in synaptic dopa mine levels (34). In con- trast, fl uctuators show larger, but short-lived, falls in 11 C-r aclopride uptake, implying that pulsatile swings in dopamine levels are occurring. As loss of dopamine terminals in PD becomes severe, the striatum fails to store dopamine and buff e r synaptic levels when exogenous levodopa is taken. Th is is magnifi ed by the relatively g reater loss of dopamine transporters from terminals, the route for dopamine reuptake, compa red with dopa decarboxylase activ- ity (35). Pulsatile swings in synaptic dopamine levels w ill promote internalization of dopamine receptors which are then unavail- able and so fl uc tuating treatment responses result. Th e severity of peak dose dyskinesias following oral l evodopa administration to PD patients has been shown to correlate with the rises of synapti c dopamine induced, as refl ected by levels of reductions in putaminal 11 C-raclopride bind ing (29). Glial-derived neurotrophic factor (GDNF) is a potent neuro- trophic factor known to prevent the degeneration of dopamine neurons in rodent and primate models of PD where nigral degen - eration is toxically induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine MPTP. A small open trial showed the effi cacy of intra-putaminal infusi ons of GDNF in fi ve PD patients along with 16 \200\22326% increases in 18 F-dopa storage a t the site of the catheter tip (43). However, a randomized placebo-controlled study in 36 c ases failed to show a clinical ben- efi t of this procedure although, again, consistent loc al increases in 18 F-dopa storage were seen (44). Th ese restorative trials suggest that in creasing dopamine storage capacity by implanting fetal cells, or via inducing terminal spro uting with trophic factors, is not enough to guarantee a therapeutic response unless approp riate connectivity is also established. Non-motor complications of PD A majority of PD patients experience depressive symptoms. It has been suggested that serotonergic loss might contribute to depres- sion in PD; to date, however, the results from neuroimaging stud- ies have not supported this view. PD patients with and without depression have shown similar median raphe uptake of 11 C-WAY 100635 bindi ng, a marker of 5HT1A sites on serotonergic cell bod- ies (45). Midbrain uptake of 123 I- -CIT refl ects serotonin trans- porter availability and does not diff er between PD patie nts with and without depression or correlate with Hamilton Depression Rating Scale scores ( 46). Th e PET tracer 11 C-RT132 binds with similar affi nity to dopamine and noradrenaline transporters. Th e striatum contains high densities of adenosine A2A sites which are found on striatal ne urons of the indirect pathway and regulate its activity. Uptake of 11 C-SCH442416, a marker of A2A binding, is normal in the striatum of non-dyskinetic subjects but is raised in dysk inetic cases (36). N -methyl- d -aspartate (NMDA) receptors are a subclass of glutamate rec eptors containing a voltage-gated ion channel which is opened during learning and memory ta sks. 11 C-CNS5161 PET is a marker of NMDA ion channel activity, and recently this has been shown to be increased at the time PD patients are experiencing levodopa-induced dyskinesias (37). Th is could help to explain the benefi cial mode of action of amantadine, an NMDA ch annel blocker. Oxford Textbook of Movement Disorders 48 Cardiac sympathetic function 123 I meta-iodobenzyl guanidine ( 123 I-MIBG) SPECT is a marke r of adrenergic terminal function and can be used to study func- tional integrity of cardia c sympathetic innervation in PD. Th e mediastinal 123 I-MIBG signal is reduced in a majorit y of PD cases, even when no clinical evidence of autonomic failure is present. However, in stage 1 PD 50% of cases still show normal cardiac MIBG uptake, so this approach is not as s ensitive a marker for PD as DAT imaging (54). Remy and co-workers used 11 C-RT132 PET to assess PD patients with and without depression ( 47). Th e depressed PD patients had lower 11 C-RT132 binding in the locus coeruleus and are as of the limbic system than non-depressed PD patients. Th is fi nding sug- gests that loss of limbic dopamine and noradrenaline rather than serotonin may be most relevant to the pat hogenesis of depression in patients with PD. Eighty per cent of PD patients will develop dementia if they survive for 20 years with thei r illness. Th is can refl ect both the presence of cortical Lewy body disease and the degen eration of dopaminergic and cholinergic projections to cortical areas. Cholinergic terminal function can be assessed with 11 C-NMP4A PET, a marker of acetylcholine sterase activity. Non-demented PD patients show focally reduced cholinergic function in parietal and occipita l cortex. When dementia is present, PD cases manifest a global and more severe reduction of cortical 11 C-NMP4A binding (48). Cortical acetylcholinesterase activity correlates with M MSE scores and performance on executive tests such as card sorting and trail making in PD ( 49). Th ese results suggest that progressive cognitive impairment in PD is in part a conseq uence of choliner- gic defi cit. Atypical parkinsonian syndromes Multiple system atrophy (MSA) 18 FDG PET studies in MSA sho w reduced levels of striatal, brain- stem, and cerebellar glucose metabolism, in contrast t o PD where these are preserved (55,56). Th e presynaptic dopaminergic system is impaired in a similar way to PD so that, while 18 F-dopa PET, VMAT2, and DAT imaging can separate PD a nd MSA from nor- mal, they cannot reliably discriminate these two parkinsonian con- ditions (18). Unlike PD, MSA is associated with loss of putamen dopamine D2 binding (Fig. 6.5), but this is mild and does not provide a sensi- tive discriminator of MSA from PD. In one series 123 I-IBZM SPECT detected reduced striatal D2 binding in only two-thirds of de novo parkinsonia n patients who had a negative apomorphine response and were thought to have possible MSA (5 7). Levels of 18 F-2-fl uoro-2-deoxyglucose ( 18 FDG) uptake refl ect neuronal synaptic activit y. In non-demented PD patients corti- cal FDG uptake is generally within normal limits, but covariance analysis reveals an abnormal profi le of relatively increased lenti- form nucle us and reduced frontoparietal metabolism (50). Th is has been labeled the PD-related profi le (PDRP), and its degree of expression correlates with degree of motor disability. Th e PD RP normalizes aft er successful treatment with dopaminergic drugs or deep brain stimulation . Frankly demented PD patients show an Alzheimer \200\231s disease (AD) pattern of impaired brain glucose utilization, with the posterior cingulate, parietal, and temporal associatio n areas being most aff ected (51). It remains unclear whether the pattern of glucose hypome tabolism in demented PD patients refl ects coincidental AD, cortical Lewy body disease, los s of cholinergic projections, or some other degenerative process. In cases proved to have c ortical Lewy body disease there tends to be greater occipital cortex hypometabolism than in Alzheimer patients (52). Th e PET ligand 11 C-PIB, a neutral thiofl avin-T ana- logue deve loped to image -amyloid plaques in AD, has recently been employed to assess PD patients with dementia. Only a minority of these cases showed increased 11 C-PIB uptake, sug- gestin g that amyloid pathology is not a major contributor to their cognitive problems (53). 123 I-MIBG SPECT, a marker of adrenergic terminal function, is normal in MSA as the autonom ic dysfunction results from loss of pre- rather than post-synaptic innervation (58). Th is diff eren- tiates MSA from PD, where the sympathetic loss is postsynaptic, and provides ano ther means of discriminating these two conditions (Fig. 6.6). Progressive supranuclear palsy (PSP) PSP is characterized pathologically by neuronal loss i n the sub- stantia nigra, pallidum, superior colliculi, brainstem nuclei, and peri-aqueduct al gray matter, with intra-neuronal neurofi brillary tangle formation. FDG PET reveals depr essed frontal cortex, basal ganglia, cerebellar, and thalamic glucose metabolism in PSP whi ch correlates with disease duration and performance on psychometric tests of frontal functi on (18, 59). Th e presence of reduced striatal metabolism sensitively discriminates 90% of PSP cases from PD. However, as striatal hypometabolism is also a feature of MSA, FDG PET ca nnot reliably discriminate these atypical conditions. (a) (b) Fig. 6.6 123 I-MIBG images of cardiac sympathetic function in (a) PD and (b) MSA. (Picture from S. Braune et al. Neurology 1999; 53: 1020 \200\2235) CHAPTER 6 Movement Disorders: Structural and Functional Imaging 49 Th e pathology of PSP uniformly targets nigrostriatal dopamin- ergic projections and so, in contrast to PD and MSA, putamen and caudate 18 F-dopa uptake and DAT binding are equivalen tly reduced, resulting in a uniform loss of striatal signal (60). Striatal D2 binding is re duced in a majority of PSP cases and this can be detected with 11 C-raclopride PET or IBZM SPECT (18). resting state, but local injury causes them to activate and swell, expressing HLA antigens on the cell surface and releasing cytokines such as IL1 and TNF . Th e mitochondria of a ctivated microglia express the translocator protein (TSPO) which is a steroid trans- porter although it was previously known as the peripheral benzodi- azepine site. 11 C-PK11195 is an isoquinoline which binds selectively to the TSPO and so provides an in vivo PET marker o f microglial activation. Involuntary movement disorders Huntington \200\231s disease (HD) and other choreas HD is an autosomal dominantly transmitted disorder associ- ated with an excess of CAG triplet repea ts (>38) in the hunt- ingtin ( HTT ) gene on chromosome 4. Other degenerative disorders ass ociated with chorea include neuroacanthocytosis (NA), dentatorubral-pallidoluysian atrophy (DRPLA), and benign familial chorea (BFC). Th e infl ammatory disorders systemic lupus eryt hematosus (SLE) and Sydenham \200\231s chorea are also associated with chorea, as is chroni c neuroleptic exposure. Post-mortem studies of HD brains have shown a signifi cant accumulation of activated microg lia in the basal ganglia and the frontal cortex. HD patients show signifi cant increases in striatal 11 C-PK11195 binding (Fig. 6.7b) which correlate with clinical disease severity m easured with the Unifi ed Huntington \200\231s Disease Rating Scale (UHDRS), with striatal reductions in 11 C-raclopride binding, and with the size of the patients \200\231 CAG tripl et expansion (68). Increased striatal and cortical 11 C-PK11195 binding can also be seen in many adult pre-manifest HD gene carriers, suggesting that microglial activation is an earl y event. Taken together, the fi nd- ings from post-mortem and neuroimaging studies support the view that activated microglia contribute to the ongoing neuronal degen- eration in HD. Clinically aff ected HD patients show severely reduced striatal lev- els of resting glucose metabolism as do NA, DRPLA, and some BFC patients (61 \200\22363). In contrast, striatal g lucose metabolism is normal in infl ammatory or tardive choreas. Th e medium spiny striatal neu- rons that degenerate in HD express D2 receptors. 11 C-raclopride PET studies show tha t striatal D2 binding is reduced by at least 30% when HD patients manifest symptoms (64, 65 ). Reduced striatal 11 C-raclopride binding is also seen in NA but, in contrast, normal str iatal D2 binding is found in SLE and tardive choreas (66). Dystonia FDG PET shows normal levels of resting glucose metabolism in DYT1 carriers but cov ariance analysis reveals an abnormal rest- ing metabolic profi le where levels of lentiform nucleus glucose metabolism are relatively reduced and frontal metabolism is raised (14). T h is pattern is seen whether DYT1 gene carriers are clinically aff ected or asymptomatic, a nd is a pattern that is almost the reverse of that reported for Parkinson \200\231s disease . A PET study of DYT1 dys- tonic patients performed while they slept also showed this abnor - mal profi le of resting glucose metabolism, confi rming that it is not movement-related. A similar profi le has been reported in DYT6 dystonia and essential blepharospasm. Th ese f i ndings suggest that dysfunction of a common network involving the basal ganglia and front al cortex may underlie all genetic dystonias. Around 50% of pre-manifesting adult HD gene carriers show reduced levels of striatal glucos e metabolism and D2 binding, indicating that their disease is already active (67). Th e rat e of pro- gression of HD can be tracked using PET as a biomarker. Caudate glucose metabolis m has been reported to decline by 3% per annum, while striatal D2 binding declines by 3 \200\2236%. Th ese fi ndings suggest that functional imaging could provide an objective mea ns of fol- lowing HD progression in the event of eff ective neuroprotective or restorative interventions being found. 18 F-dopa PET and 123 I- -CIT SPECT studies have shown normal dopamine storage in the ma jority of idiopathic torsion Microglia constitute 10 \200\22320% of white cells in the brain and form its natural defens e mechanism. Th ey are normally in a (a) (b) Fig. 6.7 11 C-PK11195 PET scans of (a) a healthy subject and (b) HD gene carrier. Mild micr oglial activation is seen in the thalamus of the healthy control whereas signi \201 cantly raised activation is evident in the frontal cortex and striata of the HD patient. (Picture courtesy of Dr Nicola Pavese) Oxford Textbook of Movement Disorders 50 dystonia (ITD) cases. In contrast, PET and SPECT have shown that striatal D2 binding is red uced (69, 70). Th is could conceiv- ably lead to decreased activity of the indirect striato pallidal pathway which normally acts to inhibit unwanted movement or actions. Recently it h as been reported uptake of 11 C-fl umazenil, a marker of benzodiazepine receptor binding on the GABA A complex, is reduced in motor and pre-motor areas in a group of DYT1 cases and c ases with sporadic dystonia (71). Such a defi cit in GABAergic function could result in a f ailure of normal corti- cal inhibitory circuits, also allowing involuntary muscle contrac- tions to occur. Imaging potentially enables PD and HD progression to be object- ively monitored and the eff i cacy of putative neuroprotective and restorative approaches to be evaluated. However, dir ect eff ects of any intervention on the imaging modality can be a confound. \227\206 FDG PET reveals a common abnormal profi le of resting glucose metabolism in the genetic dys tonias. \227\206 PET can detect striatal infl ammation (microglial activation) in pre-manifesting HD gene ca rriers and this may act to drive neu- ronal loss. \227\206 References 1. Brooks DJ . Technology insight: imaging neurodegeneration in Parkin- Dopa-responsive dystonia (DRD) and dystonia \200\223parkinsonism Dominantly inherited DRD i s related to a mutation in the DYT5 gene coding for GTP cyclohydrolase 1. Th is enzyme cons titutes part of the tetrahydrobiopterin synthetic pathway, the co-factor for tyrosine hydro xylase. Patients are unable to manufacture levodopa, and hence dopamine, from endogenous ty rosine but can still con- vert exogenous levodopa to dopamine. DRD cases generally present in childhood with diurnally fl uctuating dystonia and later develop background parkinsonism . Occasionally, the condition presents as pure parkinsonism in adulthood. 18 F-dopa PET and 123 I- -CIT SPECT fi ndings are normal in most DRD patients (72), thus distin- guishing this condition from early-onset dystonia \200\223parkinsonism where severely reduced putam en 18 F-dopa and 123 I- -CIT uptake is found (73). son \200\231s disease. Nature Clin Pract Neurol 2008; 4 : 267 \200\2237 7 . 2. Vaillancourt DE, Spraker MB, Prodoehl J, et al. High-resolutio n diff u- sion tensor ima ging in the substantia nigra of de novo Parkinson disease. Neurology 2009; 72 : 1378 \200 \2238 4 . 3. Schrag A, Good CD, Miszkiel K, et al . Diff erentiation of atypical parkin- sonian syndr omes with routine MRI. Neurology 2000; 54: 697 \200\22370 2 . 4. Brooks DJ, Seppi K, for th e Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of mu ltiple system atrophy. Mov Disord 2009; 24 : 949 \200\2236 4 . 5. Seppi K, Schocke MF, Esterhammer R, et al. Diff usion-weighte d imag- ing discriminates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple syst em atrophy. Neurology 2003; 60 : 922 \200\2237 . 6. Nicoletti G, Lodi R, Condino F, et al . Apparent diff usion coeffi cient meas- urements of the middle cerebellar peduncle diff erentiate the Parkinson variant of MSA from Parkinso n \200\231s disease and progressive supranuclear palsy. Brain 2006; 129 : 2679 \200\2238 7 . 7. Berg D, Siefk er C, Becker G . Echogenicity of the substantia nigra in Parkinson \200 \231s disease and its relation to clinical fi ndings. J Neurol 2001; 248 : 684 \200\2239 . Conclusions Structural imaging 8. Berg D, Merz B, Reiners K, Naumann M, Becker G . Five-yea r follow-u p study of hyperech ogenicity of the substantia nigra in Parkinson \200\231s disease. Mov Disord 2005; 20 : 383 \200\2235 . Structural changes in PD nigra can be detected with both trans- cranial sonography and diff usion tensor MRI. \227\206 9. Walter U, Klein C, Hilker R, et al. Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 2004; 19 : 1445 \200\2239 . Midbrain hyperechogenicity reveals a susceptibility to PD rather than correlating with seve rity of disease. \227\206 10. Sommer U, Hummel T, Cormann K, et al. Detection of presymptomatic Parkinson \200\231s d isease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 2004; 19 : 11 96 \200\22320 2 . Atypical parkinsonian syndromes can be sensitively discrimi- nated from typical PD by abnor mal putamen signals detect- able with both diff usion-weighted MRI and transcranial sonogra phy. \227\206 11. Behnke S, Berg D, Naumann M, Becker G . Diff erentiation of Parkinson \200\231s disease and atypical parkinsonian syndromes by transcranial ultrasound. J Neurol Neurosurg Psychia try 2005; 76 : 423 \200\2235 . 12. Bhatia KP, Marsden CD . Th e behavioral and motor consequences of focal lesions of the basal ganglia in man. 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