FP-CIT SPECT Th e SPECT technique most widely used in the diff e rential diagnosis of parki nsonism is dopamine transporter (DAT) imaging. Th e commercially avail able tracer 123 I-FP -CIT ( 123 I-2-carbomethoxy-3-(4-iodophenyl)- N -(3-fluoropropyl) -nortropane) (DAT-Scan) b inds specifi cally to presynaptic dopamine transporters of nigrostriatal nerve endings, and semiquantitative region of interest (ROI) based analysis of DAT-SPECT is able to identify reduced striatal tracer binding in PD and other parkinso- nian syndromes associated with de generation of the nigrostriatal projections (44). In PD, these changes are typically asymme trical and correlate with disease duration and severity of motor symp- toms (45, 46). DAT-S PECT is useful to distinguish PD from other tremor disorders without nigrostriatal neurodeg eneration, such as essential or dystonic tremor, as well as from drug-induced parkin- sonis m, psychogenic parkinsonism, and levodopa-responsive dys- tonia presenting with parkinsonis m (47). Th is imaging modality is also helpful in rejecting or confi rming a possible diagn osis of neu- rodegenerative parkinsonism in subjects with equivocal or vague symptoms or at ypical tremor presentations like unilateral postural IBZM \200\223SPECT IBZM ( 12 3 I-3-iodo-6-methoxy benzamine) is a ligand which specifi call y binds to D2-receptors, enabling visu- alization of postsynaptic dopamine receptors within the striatum. Based on the sparing of striatal neurons in the pathology of PD and their in volvement in other types of degenerative parkinsonism, such as MSA and PSP, postsynaptic do pamine receptor imaging has been proposed as a diff erential diagnostic tool (50). In early untreated PD patients, IBZM-SPECT studies revealed a relative increase in D2-binding, espe cially in the putamen contralateral to the more aff ected body side (51). In contrast, trac er uptake seems to be reduced even in the earliest stages of atypical parkinsonian conditio ns such as MSA and PSP (52). However, there is consider- able overlap, particularly in earl y disease stages, where clinical dif- ferentiation is the most diffi cult, such that postsy naptic dopamine CHAPTER 8 Overview of parkinsonism and approach to differential diagnosis 69 (a) (b) (c) (d) (e) (f) Fig. 8.3 (a) Normal MRI in a patient with idiopathic PD; (b) putaminal atrophy and putamina l hypointensity in a patient with MSA; (c) vascular lesions in a patient with vascular park insonism; (d) mid-sagittal T 1 -weighted MRI in a patient with idiopathic PD; (e) mid-sagit tal T 1 -weighted MRI in a PSP patient, exhibiting marked midbrain atrophy without signi \201 cant pontine atrophy (divided by white line) forming the silhouette of a penguin or co libri; (f) asymmetric parietal atrophy in a patient with CBS. D2 receptor SPECT imaging has limited value in clinical practice, although high predictive values have been reported for the com- bined application of IBZM-SPECT and FP-CIT SPECT in the eval- uation of PD and MSA (53). hyperechogenicity in the substantia nigra (SN) region of the mid- brain with this technique (see Fig. 8.4), but this is not the case in patients with PSP and MSA who, unlike PD patie nts, have been reported to show increased areas of echogenicity in the lenticular nucleus ( 55). A recent study has proposed that hyperechogenicity of the SN in combination with norma l echogenicities in the len- ticular nucleus discriminates PD from PSP and MSA with a posi- tive predictive value of over 90% (56). In addition, another recent study has demonstrated that midbrain hyperechogenicity is able to distinguish between PD patients and SWEDD patie nts (57). While these observations are certainly of great interest, the precise role of TCS in the diagnostic work-up of parkinsonism in clinical practice still needs to be defi ned. MIBG-SPECT 123 I-MIBG (meta-iodobenzyl guanidine), an analog of norepinephrine, is a tracer used to assess sympa- thetic cardiac innervation, which is signifi cantly reduced even in early PD, while postganglionic sympathetic eff erents are spared in MSA. Th erefore MIBG-SP ECT is potentially useful in the diff erential diagnosis of these types of degenerative par - kinsonism, with reduced binding in PD versus normal cardiac uptake in MSA. However, there can be false-negative results in patients with PD without signifi cant autonomic nervous s ystem involvement (54). Principles of management Th e therapeutic management of parkinsonian disorders is complex a nd oft en involves multidisciplinary approaches combining medical therapies with non-pharma cological measures such as physiotherapy, speech therapy, or psychosocial counseling. In Transcranial sonography Transcranial sonography (TCS) can visualize the butterfl y-shaped s tructure of the midbrain using an acoustic temporal bone window. About 90% of patients with idiopathic PD show increased areas of Oxford Textbook of Movement Disorders 70 (a) (b) Fig. 8.4 (a) TCS visualization of the butter \202 y-shaped structure of the midbrain in a healthy subject; (b) hyperechogenicity of the substantia nigra in a patient with idiopathic PD. addition, deep brain surgery has become an important modal- ity for a subset of PD patients with drug-related complications. Details of these diff erent approaches and their indicati ons for the miscellaneous forms of degenerative and secondary parkinsonism can be found in the respective chapters of this volume. In princi- ple, all available therapies for degener ative parkinsonian disorders are symptomatic, and so far no approach has been proved to slo w or halt the underlying progression of disease. Th is can be diff er- ent for some seconda ry types of parkinsonism where removal of a causative drug or tumor or eradication of an un derlying infection (see Table 8.1) may even lead to complete remission. Despite all recent advances in the drug treatment of parkinsonism, levodopa substitution has remained the gold standard of symptomatic effi - cacy for PD, and is oft en at least partially eff ective in other types of degenerative or secondary parkinsonism. However, the magnitude of response is most pronounced in PD, such that levodopa respon- siveness is part of the clinical diagn ostic criteria of PD. Th erefore, depending on the results of the diagnostic work-up, a tri al of levo- dopa will be part of the treatment approach in most patients pre- senting with parkinsonism. clinically but with \200\230scans without evidence of dopaminergic defi - cit \200\231 (59 ). Perhaps even more importantly, advanced MRI has shown promise of diff erentiating betwee n the diff erent types of degen- erative parkinsonism early in the disease course, and tran scranial ultrasound has entered the stage as a potential novel diagnostic imaging tool. Future developments A key priority of clinical research in parkinsonian disorders is again driven by the PD field and is likely to lead to new concepts for early diagnosis and at-ris k definition, including \200\230pre- motor \200\231 signs of disease as well as molecular and imaging markers. Biomarkers for the different degenerative parkinsonian syn- dromes are also a major requirement for improved differential diagnosis, and studies of their progres sion include clinical trials of disease-modifying agents. Genetic and proteomic markers dis - tinguishing between the different neurodegenerative disorders associated with parkinsonis m are evolving, with some showing promising sensitivities and specificities (60, 61). High- field MR holds the promise of detecting early PD with high sensitivity and specificity (62) , and transcranial ultrasound is being sug- gested as a future tool for screening for PD ri sk in the general population (63). Key advances Th e most important advances in the fi eld of parkinsonism in recent years hav e been related to the genetics of PD and insights into pathophysiological pathways developi ng out of genetic discover- ies (see Chapter 7). Clinicopathological studies have re-focuse d on clinical diff erential diagnosis between diff erent types of degenera- tive parkinsoni sm, recognizing a parkinsonian variant of PSP (28) that can initially closely mimic PD, as well as the impossibility of reliably distinguishing between the tauopathies of PSP and CBS on clinical grounds alone (58). Important advances have also been made in the use of neuro imaging to aid diff erential diagnosis of par- kinsonism, where dopamine transporter SPECT has become a rou- tine clinical tool for distinguishing between PD and atypical tremor of o ther etiology, and has introduced the new diagnostic concept of SWEDDs for patients present ing with signs of parkinsonism Conclusions Diagnosing idiopathic PD can be a straightforward clinical exer- cise in cases presenting with a typical history and classical clinical features which subsequently show a n excellent response to levo- dopa. In many cases, however, a patient with new-onset parkin son- ism will require consideration of a broad spectrum of diff erential diagnoses, and dia gnostic accuracy will oft en remain suboptimal. Judicious use of structural and functional neuroimaging tech- niques will oft en enhance accuracy of early diagnosis. Although in the case of PD this can be further refi ned by genetic testing in those with a family history a nd/or young onset of disease, there CHAPTER 8 Overview of parkinsonism and approach to differential diagnosis 71 is no immediate management implication emanating from such testing and it is not currently part of routine diagnostic work-up. Simple as the elementary clinical defi nition of a park insonian syn- drome may be, diff erential diagnosis of parkinsonism continues to require co nsiderable clinical acumen in terms of careful assess- ment and weighing of the details in the history and the clinical fi ndings as well as making optimal use of ancillary tests, av oiding unnecessary over-investigation. Even in the hands of movement disorder experts, clin ical diff erential diagnosis between the early stages of PD and atypical degenerative parki nsonian disorders is oft en diffi cult, if not impossible, such that there is need for furt her refi nement of diagnostic molecular or imaging markers for the dif- ferent diseases. 8. Nalls MA, Plagnol V, Hernandez DG, et al . Imputation of sequence variants for identifi cation of genetic risks for Parkinson \200\231s disease: a meta-analysi s of genome-wid e a ssociation studies. Lancet 2011; 377 : 641 \200\2239 . 9. Alexander GE, DeLong MR, Strick PL . 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CHAPTER 9 Parkinson \200\231s Disease: Premotor Features, Diagnosis, and Early Management A nthony H.V. Schapira and David Gallagher Introduction Parkinson \200\231s disease (PD) is a neurodegenerative disease, the ini- tial clinical features of which are the result of loss of dopaminer- gic neurons in the substan tia nigra pars compacta (SNc) of the midbrain. As the disease progresses the involvement of additional brain areas in the degenerative process produces predominantly non-dopaminergic , non-motor features (e.g. cognitive decline and autonomic dysfunction). Although the class ic clinical triad of bradykinesia, rigidity, and tremor still defi nes PD and enables a dia gnosis, it is recognized that the disease process has evolved for many years if not decades , before these clinical features appear. Certain non-motor symptoms may appear before a dia gnosis of PD can be made and these may represent risk factors for the disease or even prodr omal PD. Th ese features include hyposmia, rapid eye movement (REM) sleep behavior disorder (RBD), depression, and constipation. interaction, and nerve trophic factor depletion (3). Th e exact role of LBs in this process , whether toxic, neuroprotective, or an epi- phenomenon, remains unclear. Nonetheless, auto psy studies of the topographic distribution of alpha-synuclein pathology provide important insights into neuroanatomical correlates of non-motor symptoms in PD and their temporal rel ationship to the onset of motor symptomatology. Braak and colleagues (2) have proposed a se quential staging of LB pathology in PD. Stage I involves the anterior olfactory structures and dorsal motor nucleus of the vagus (lower medulla). Involvement of the olfactory bulb an d vagal nucleus have been proposed as neuropathological correlates for olfactory impairment and autonomic dysfunction (particularly gas- trointestinal), respectively, which commonly occur in early PD and during the premotor phase of the disease. Stage II involves LB dep- o sition in a number of brainstem nuclei, including the locus coeru- leus, lower raphe nuclei , and reticular formation, but confi ned to the medulla and pontine tegmentum. Th ese patho logical changes have been implicated in the development of RBD and mood dis- orders in earl y PD. It is only during stages III \200\223IV that, according to the Braak staging hypothes is, LBs appear in the substantia nigra pars compacta. In more advanced disease (stages V an d VI) diff use deposition of LBs in neocortical structures can occur. Th e discovery of dopamine defi ciency in PD in the 1960s and the subsequent introduction o f levodopa have provided patients with a signifi cant improvement in both quality of life a nd life expectancy, but the treatment of non-motor features and slowing of disease progress ion remain important unmet needs. Th us the prodromal period of PD, in both its molecular a nd clinical perspectives, has become a major focus of attention of research (1). However, it must be recognized that the caudal \200\223rostral Braak concept refers to LB d eposition and not neuronal degeneration, and the first sites to undergo actual neuronal los s are the SNc and premotor cortex. Furthermore, the pattern of LB spread described by Braak is thought to be seen in only half the autop- sied cases of PD. Also, LB pathology is not unique to PD and related disorders (the alpha-synucleinopathies, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), but can also occur in other degenerative neurolo gical conditions, including neurodegeneration with brain iron accumulation (NBIA), subacute sclerosing panencephalitis, and Alzheimer \200\231s disease. Therefore LB formation may re present a non-specific Pathology of Parkinson \200\231s disease Pathologically, PD is characterized by the loss of dopaminergic neurons in the SNc and the presence of alpha-synuclein-containing inclusions, Lewy bodies (LBs), and Lewy neurites, which can occur at a number of extra-nigral location s and involve non-dopaminergic neurotransmitter systems (2). Th e pathogenesis of PD is com plex and involves mitochondrial dysfunction, oxidative stress, and free-radical-mediated ne uronal damage, ubiquitin proteasome system (UPS) defects, excitotoxic cell damage, oligoden drocytic Oxford Textbook of Movement Disorders 74 downstream process encountered in different neurodegenera- tive disorders. with the top two quartiles (13). In a two-year longitudinal study of fi rst-degree relative s of patients with PD, olfactory testing was used to select normosmic and hyposmic individu als who then under- went dopamine transporter (DAT) single photon emission com- puted tomog raphy (SPECT) (14). At two years, 10% of the hyposmic group who had shown markedly reduced DAT binding on SPECT imaging at baseline had developed clinical PD. In the remainder of the hyposmic group, despite no clinical evidence of parkinson- ism, DAT binding had decreased more than in normosmic con- trols. In a further study of 30 subjects with idiopathic hyposm ia, 11 demonstrated hyperechogenicity of the substantia nigra on transcranial sonography, b ut the majority had no motor features or signs suggestive of PD. Despite this, DAT SPECT wa s abnormal in fi ve subjects and two had borderline binding ratios (15), suggestive of poss ible premotor PD. Prodromal or premotor clinical features of Parkinson \200\231s disease Clinical features su ch as hyposmia, RBD, depression, and con- stipation can occur relatively commonly in the pr emotor, prediagnostic phase of PD (4). For example, in a large retrospec- tive case-notes a nalysis of 433 pathologically proven PD patients, 21% had exclusively non-motor symptoms at presentation to their general practitioner, and of these 53% presented with pain, 16.5% wi th urinary problems, 12.1% with depression or anxiety, 5.5% with non-specifi c cognitive im pairment without functional limita- tion or dementia, and 4.4% with fatigue (5). A number o f patients in this study had inappropriate specialist referrals (orthopedics, rheumatology, psychiatry, and urology), leading to unnecessary diagnostic and therapeutic interventions and delayed diagnosis of PD. Th e University of Pennsylvania Smell Identifi cation Test (UPSIT), a 40-item odor identifi cation test, has been extensively studied in PD. In a study of early PD (mean Hoehn and Ya hr stage 1.4), a strong correlation between UPSIT scores and DAT SPECT imaging indices in t he striatum as a whole (regression coeffi cient 0.66, p = 0.001), and particularly the puta men (0.74, p < 0.001), was dem- onstrated (16). Extrapolation of these fi ndings into the p remotor phase of PD is supported by epidemiological studies of smell loss antecedent to cli nical PD and is consistent with the topographical distribution of LB in anterior olfactory structures in autopsy studies of early PD, suggesting a potential role for smell testing in the early diagnosis of PD. Risk association genes Th e results of genome-wide association studies for PD confi rm that alpha-synuclein, tau, and histocompatibility genes are risk factors for idiopathic/sporadi c PD (6 \200\2238). Evidence is accumulat- ing that glucocerebrosidase (GBA) mutations are numerically the most important risk factor for PD. Several studies have shown that GBA muta tions are seen more commonly in PD patients than in age-matched controls (9). Th e Ashkenaz i Jewish population has a particularly high frequency of PD related to GBA mutations (10). Th e link between GBA and PD has been reinforced by the increased frequency of mutations in post-mortem confi rmed LB-positive PD (11). Th e published frequencies of GBA mutations in PD are likely to be an underestimate, as most studies have only tested for the two most fr equent GBA mutations causing Gaucher \200\231s disease. Numerous mutations of the GBA gene impair enzyme activity and cause Gaucher \200\231s disease, and there may be GBA sequence c hanges that are exclusive to PD. As a conservative estimate, GBA mutations are associated w ith a fi ve- to tenfold increase risk for PD. UPSIT scores are signifi cantly lower in PD than in both vascular parkinsonism and controls (17). In a study where olfaction in PD was compared with atypical parkinsonian syndromes ( 18), UPSIT scores were normal in progressive supranuclear palsy (PSP) and corticobasal dege neration (CBD) compared with controls, and there was only mild impairment in MSA. However, UPSIT scores were markedly reduced in the PD group and demonstrated good sensitivity (77%) and specifi city (85%) in diff erentiating PD from atypical parkinsonism. Sleep disorders and restless legs syndrome RBD is a parasomnia characterized by dream enact ment and loss of muscle atonia during REM sleep. Patients may be vocal and violent, posing a risk to their bed partner. Insights into the pathophysiol- ogy of RBD have been gained fr om brainstem structural lesions in humans, post-mortem autopsy studies, and animal models. RBD has been described in case reports in association with demyeli- nation of the dorsal po ntine tegmentum, an ischaemic pontine lesion, a pontomesencephalic cavernoma, and brainstem neuri- noma (19). Incidental brainstem LB pathology has been demon- strated in an autopsie d case of RBD (20). Proposed anatomical loci of RBD in humans, extrapolated from animal mod els, include the pre-coeruleus, sublaterodorsal nucleus, and lateral pontine teg- mentum (1 9). Th ese topographical locations correspond to brain- stem regions that are involved befo re the development of striatal LB pathology (stages I and II) according to the Braak hypoth esis. Th is may provide an explanation for the high prevalence of RBD in PD, with its occur rence oft en preceding motor impairment. Several genetic causes of familial PD have been identifi ed (1, 12). However, even the auto somal dominant causes such as LRRK2 mutations have variable penetrance, with a median age o f onset in the early seventh decade. It is unclear at present whether single copies of the autosomal recessive genes predispose to PD. Current data suggest that these genetic causes account for only a small pro- portion ( 5 \200\22310%) of PD patients although, taken toget her with the genetic risk factors, they indicate that a substantial proportion of the risk for PD can be explained on a genetic basis. Despite the considerable and important advances in defi ning the genetic contribution to PD , we have not yet reached the stage where, other than in the autosomal dominant cases, gene tic profi le can be used to defi ne risk for PD. Olfaction Several epidemiological studies have suggested that impaired olfac- tion is an ea rly marker of idiopathic PD. In the Honolulu \200\223Asia Aging Study, 2267 participants ha d olfactory testing at baseline and those in the lowest quartile of olfaction had a signifi cantly increased age-adjusted risk of subsequently developing PD (odds ratio (OR) 5.2; 95% confi dence interval (CI) 1.5 \200\22325.6) compared Th ere have been a number of epidemiological studies showing an association between RBD and the development of PD or other neu- rodegenerative disorders. For example, in one study of 44 patients presenting to a sleep center with idiopathic RBD (iRBD), confi rmed CHAPTER 9 Parkinson \200\231s Disease: Premotor Features, Diagnosis, and Early Management 7 5 by polysomnography, 20/44 (45%) subsequently developed a neu- rodegenerative disorder (in a ll cases alpha-synucleinopathy \200\224PD in nine, DLB in six, and MSA in one) a mean 11.5 years aft er symp- tom onset and 5.1 years aft er formal diagnosis of RBD (21). In a second study, 57% of patients presenting to a sleep clinic with RBD had an underlying neurologica l disorder, and 52% of those with PD had symptoms of RBD preceding the development of motor symptoms (22). studies, depressed subjects had a relative risk (RR) of 3.13 (95% CI, 1.95 \200\2235.01) of subsequently developing PD compared with con- trols in the fi rst study (32), and a relati ve risk of developing PD of 2.20 (95% CI, 1.70 \200\2232.84) compared with a diabetes cohor t and 2.24 (95% CI, 1.72 \200\2232.93) compared with an osteoarthritis cohort in the second study (33). A case \200\223control study identifi ed increased prevalence of premorbid anx iety disorder in PD compared with controls, and in a large prospective study ( N = 35 815) using the Crown \200\223Crisp phobic anxiety index there was an increased risk of developin g PD (RR, 1.5; 95% CI, 1.0 \200\2232.1) in those with the highest level of anxiety at basel ine (34). Several imaging studies in iRBD have demonstrated early premotor basal ganglia changes. An imaging study assessing presynaptic DAT using 123 I-( N -3-iodopro-pene-2-yl-2 -carbom- ethoxy-3 -4-chlorophenyl tropane) ( 123 I-IPT) SPECT revealed signifi cantly reduced str iatal uptake in iRBD patients compared with controls, but less reduced than in symptomatic PD (23). 13 C-dihydrotetrabenazine positron emission tomography (PET) in patients with iRBD demonstrated reduced binding in all stri- atal nuclei, particularly the posterior putamen (24), and a cerebral perfusion study ( 99m Tc-ethylene cysteinate dimer (ECD) SPECT) in iRB D showed increased perfusion bilaterally in the pons and putamen with reduced perfusion of the frontal and temporopari- etal cortices, a metabolic picture consistent with that found in idi- opathic PD (25). Th erefore depression and anxiety may be predictive of future development of PD. Several fu nctional imaging studies in PD have demonstrated signal change in the brainstem which corre lates with clinimetric indices of mood. For example, in a study using 123 I- CIT SPECT, dorsal midbrain binding refl ecting serotoninergic function was signifi cantly correlated w ith Unifi ed Parkinson \200\231s Disease Rating Scale (UPDRS) mood and mentation scores, bu t not with motor function (35). Th ese imaging studies suggest that degeneration of seroton inergic and noradrenergic brainstem nuclei can occur in parallel or precede substantia nigr a degeneration, leading to aff ec- tive disorders in the early and premotor phase of PD. Development of dementia is common in PD, particularly in the later stages. However, a numbe r of studies using detailed neuropsy- chological assessments, including tests sensitive to frontal lobe function, have revealed that cognitive impairment, particularly dysexecutive, can occur early in PD (36). PD dementia (PDD) and DLB are distinguished by whether dementia occurs within a year of onset of motor symptoms, but this is an arbitrary distinction give n the common neuropathology (alpha-synuclein containing LB deposition) and overlapping non- motor symptomatology of the two diseases. Imaging studies in PD have revealed that disrupti on of frontal \200\223striatal dopaminergic connections can occur early in PD and are assoc iated with abnormalities in frontal executive cognitive function (37 \200\22339). Th ese studies suggest that in patients with iRBD there is a predis- position to future dev elopment of alpha-synucleinopathies, includ- ing PD and MSA, and that early striatal and co rtical metabolic changes may already be present, even years before the appearance of motor symptoms or clinical presentation of PD. Other disorders of sleep may also predict subseque nt development of PD. A large population-based study (Honolulu \200\223Asia Aging Study, N = 3078 (26)) revealed that daytime excessive somnolence was a risk factor (OR, 2.8; p = 0.0 14) for the development of PD.