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. Restless legs syndrome (RLS) is prevalent in PD, and in a propor- tion of patients precedes motor involvement (27). In a study of PD patients with RLS, PD/RLS occurred at an older ag e of onset, was less likely to be associated with a family history, and was associated with signifi cantly lower ferritin levels than idiopathic RLS (iRLS) (27). When patients with i RLS were compared with patients in the early stages of PD using 123 I-IPT SPECT, no presyna ptic dopamin- ergic neuronal loss was demonstrated in iRLS, and there was no diff erence fr om controls (28). Th e relationship between RLS and PD is most likely to represent a chance occurrence rather than a common pathogenesis. Autonomic dysfunction Autonomic features may occur early in PD and predate the onset of mot or features. Epidemiological evidence suggests that con- stipation, in particular, may be a n early premotor feature of PD. In the Honolulu Heart Program, 6790 subjects were questione d about their bowel habits, and in a 24-year follow-up period less than one bowel movement per day was associated with a greater risk of developing PD (RR, 4.1; 95% CI, 1.7 \200\2239 .6; p = 0.001) com- pared with those whose bowels were opened twice per day (40). In a retr ospective study, 44.6% of respondents described onset of constipation preceding motor sympt oms with a mean latency of 18.7 years (41). Neuropsychiatric illness and cognitive impairment LB deposition in brainstem loci, such as in the noradrenergic locus coeruleus and serotoninergic dorsal raphe nuclei, has been impli cated in aff ective disorders, and this can precede basal mid- brain involvement in PD. Th is may explain the high prevalence of depression in early PD that may precede development o f motor symptoms (29). In a systematic review of psychiatric illness pre- ceding motor symp toms in PD (30), two cohort studies, one nested case \200\223control (NCC) study, and six c ase \200\223control studies were iden- tifi ed for depression and PD. Five of the six case \200\223control studies, both cohort studies, and the NCC showed a statistically signifi ca nt association between a history of depression and subsequent devel- opment of PD. For exam ple, a large retrospective cohort study ( N = 105 406) (31) showed that, at diagnosis of PD , 9.2% of patients had a history of depression compared with 4.0% of con- trols (OR, 2.4; 9 5% CI, 2.1 \200\2232.7). In two other retrospective cohort Sexual dysfunction is common in PD and includes diffi culties with sexual arousal, reduced libido, erectile dysfunction, and anor- gasmia (42). In a large retrospective epidemiologic al study (32 616 participants), men with erectile dysfunction had increased risk of subsequ ently developing PD (RR, 3.8; 95% CI, 2.4 \200\2236.0, p < 0.0001) (43). In another study, 23.3% of men and 21.9% of women reported that premorbid sexual dysfunction contributed to c essation of sex- ual activity following diagnosis of PD (42). In a large retrospective anal ysis of patients with pathologically proven PD (5), 3.5% of ini- tial presentations were wi th urinary symptoms but without motor features of PD. Oxford Textbook of Movement Disorders 76 Orthostatic hypotension (OH) is common in PD, particularly in later disease, and can be a c onsequence of dopaminergic medi- cation. However, in a study of patients with a clinical di agnosis of PD, in whom MSA had been excluded using imaging of myocar- dial sympathetic func tion (cardiac 18 F-fl uorodopa SPECT), OH was of early onset (within a year of onset of mot or symptoms) in 60%, and preceded motor involvement in 13% (44). Autopsy examinations have revealed early involvement (LB deposition) of central (medulla oblongata) and peripheral (s ympathetic and parasympathetic) neurons that control autonomic function in PD, which may re present a pathological basis for early autonomic symptoms (45). imaging of the dopamine nigrostriatal system. It is doubtful whether any of the clinical or biochemical features described in the previous section are capable of, or indeed even nece ssary for, discriminating PD from other parkinsonian syndromes. Genetic testing may con- fi rm status in aff ected individuals in familial forms of PD, and may also identify family m embers at risk, although at the time of writing genetic testing for PD per se is not approp riate for PD. Th e most important reason for establishing an individual \200\231s risk for PD is to enabl e early and eff ective intervention to prevent the onset or slow the development or progres sion of the disease. It is estimated from autopsy studies that at least 50% of dopaminergic neurons in the SNc will have been lost at diagnosis of PD, and that there is a negative ex ponential progression of the disease (53). Th e non-linear pattern of dopaminergic cell los s is consistent with clinical and imaging studies. In a longitudinal study using 18F-fl uor odopa PET, change in fl uorodopa signal was inversely related to PD duration at baseline (5 4). In a prospective study using UPDRS as a clinical marker of disease progression, rate of deterioration in motor scores decreased with advancing disease duration (55), although it is rec- ognized that earlier-onset disease is associated with slower progres- sion (56). Gi ven that a rapid rate of SNc dopamine depletion occurs in the premotor phase, it could be i nferred that, to derive most benefi t, any potential disease-modifying therapy should be st arted before the onset of motor symptoms. Neuroimaging in the premotor diagnosis of Parkinson \200\231s disease All the symptoms desc ribed so far are relatively non-specifi c, occurring both in the general elderly population and in other neurodegenerative diseases including non-PD parkinsonism, and in the case of hyposmia in Alzheimer \200\231s disease (46 \200\22349). However, a composite of clinical p remotor features may allow stratifi cation for risk of future development of neurodegenerat ive disorders suf- fi cient to direct appropriate use of imaging techniques to identify tho se with premotor dopamine defi cits (50). SPECT imaging using ligands which bind to presyna ptic DAT is widely used in practice to help diagnose PD, particularly in early disease or i n patients presenting with subtle or atypical features. But DAT SPECT imag- ing could also have a role in presymptomatic diagnosis of at-risk individuals, for example those with susc eptibility genes, hyposmia, or other premotor features. Other recent developments in imagin g in PD include transcranial sonography. Hyperechogenicity of the substantia nigra on sonog raphy has been demonstrated as an early marker of PD and is present in monogenetic forms of PD in the preclinical phase (51). However, substantia nigra hyperechogenic- ity has been s hown in up to 10% of normal subjects, and the nigra cannot be visualized in a similar propo rtion, limiting the diagnostic utility of the test. Cardiac sympathetic denervation is a fe ature of Lewy body disorders, and extra-striatal imaging modalities, such as meta-iodobenzy l guanidine (MIBG) SPECT, have been demon- strated to be abnormal in early PD (52). Th e diagnosis of Parkinson \200\231s disease Motor features of PD Th e classic early featu res of PD are bradykinesia, rigidity, and tremor. Postural instability and several addition al motor and non-motor symptoms usually develop later in the disease. Bradykinesia manifests in several ways, including diffi culty or delay in initiating volunt ary movement, multitasking, or undertak- ing rapid motor tasks in sequence. A poverty of mo vement becomes evident, especially to family and friends. Th is may be represented by a red uction in spontaneous gestures, decreased facial movement, and blinking. Involvement of the limbs may be seen, with impaired fi ne movements of a hand and in the dominant hand leads to pro- gressive micrographia. Th ere are problems with fastening buttons or brassieres, ty ing laces, and using a screwdriver. Th e patient \200\231s gait becomes slow, small-stepped, and shuffl ing, with the patient s ometimes \200\230chasing his own center of gravity \200\231. Th e arm on the aff ected sid e does not swing as much as the contralateral arm. Th e patient may complain of diffi culty turning over in bed or rising from a chair. Freezing usually occurs later in the course of PD, but some patients experience \200\230gait ignition failure \200\231 especially when a pproaching a doorway. Biochemical markers for Parkinson \200\231s disease Insights into the pathogenetic pathways involved in PD have enabled a number of candidate peripheral assays to be considered as po ten- tially useful for calculating risk for PD. Blood markers for oxidative stress, includi ng uric acid or urinary 8-dihydroxydeoxyguanosine, or platelet mitochondrial complex I acti vity may be abnormal in a proportion of cases. Whilst no single assay could distinguish PD from normal, a composite \200\230basket \200\231 of assays which might also include periph eral or cerebrospinal fl uid (CSF) alpha-synuclein or DJ-1, together with the genetic marke rs and prodromal clinical features described above, might together help defi ne and refi ne a population considered at high risk for PD. Physical examination for bradykinesia will evaluate rapid alter- nating movements in the up per and lower limbs and, in idiopathic PD, show asymmetry of speed, amplitude, and rhythm i n the early stages. Examples of helpful maneuvers include fi nger- or heel-tapping, pronati on \200\223supination of the outstretched arms, and rapid fl exion \200\223extension of the extended fi ngers at the metacar- pophalangeal joints. Th e relevance of early diagnosis in Parkinson \200\231s disease At present, the diagnosis of PD is predominantly based on clinical criteria which may, in appropriate circumstances, be supported by Rigidity represents an increase in tone which is present through- out the range of movement and is independent of the speed at which the limb is moved. Th e tremor of PD may superimp ose upon rigidity to produce cogwheeling, and this phenomenon may be absent if there is no tremor. Examination of the wrist with gentle CHAPTER 9 Parkinson \200\231s Disease: Premotor Features, Diagnosis, and Early Management 7 7 fl exion \200\223extension movements is the best way to elicit cogwheeling, and this can be repeated at the elbow. Rigidity aff ects the patient \200\231s posture, producing a fl exi on at most joints including the spine which results in the simian posture typical of PD. An extreme form of this is known as camptocormia (57). Postural abnormalities also aff ect th e distal limbs, with extension of the fi ngers and fl exion of the metacarpophalangeal join ts or dorsifl exion of the great toe (striatal hand or toe). problems at night with nocturia, which when associated with bradykinesia during nocturnal O FF periods causes considerable discomfort. Pain is a frequent symptom in PD, and some patients manifest especially with shoulder pain. Pain, anxiety, akathisia, respiratory distress, depressive mood swings, and slowed and imp aired thought are symptoms which may be experienced during OFF periods and which will respo nd, at least in part, to dopaminergic therapy (74). Th e development of an asymmetric intermittent resting tremor at 4 \200\2236 Hz is estimate d to be a presenting feature in 70% of PD patients. In addition, there is oft en a small-am plitude postural tremor at a higher frequency ( 12 Hz). Th e resting hand tremor is referre d to as \200\230pill-rolling \200\231, in the style of the pharmacists of the nineteenth c en- tury who would prepare their tablets by hand. A tremor may aff ect other parts, includi ng the foot or leg (in which it may fi rst mani- fest), lips, jaw, and tongue (58). A head tremor, titubation, is more suggestive of essential tremor. Th e resting tremor is exacerba ted by physical or emotional stress, and in the early stages can be voluntar- ily inhibited for short periods. Th e tremor usually becomes bilateral aft er about fi ve or six years, although the tremor in the fi rst aff ected side generally remains more severe (59). Treatment of early PD Following a secure diagnosis of PD, it is important to educate the pa tient accordingly in the nature of their illness and the treatments available to them, as w ell as lifestyle changes that may be appro- priate. Contact with an established national pa tient organization is oft en invaluable. Lines of communication to the patient \200\231s pr imary physician should be clearly established, and the patient should be provided with info rmation on specialist nursing and physician care. Non-pharmacological therapies for PD are important. Exercise therapy can improve and mainta in function in PD patients, and should be encouraged. Laboratory studies suggest that exerc ise might also have protective eff ects on disease progression, but this remains to be esta blished. It is also important for patients to main- tain social and intellectual activities . Th e needs of the caregiver should also be considered. Th eir work load may be dramatical ly increased by caring for a person with PD, and there is an increased incidence of depress ion. Non-motor features of PD Th e widespread and progressive neurodegeneration in the PD brain leads to the emergence of a variety of features that are col- lectively grouped under the t itle of non-motor symptoms. Some of these have already been discussed, as their emergence m ay precede motor symptoms and signs. Th e non-motor symptoms of PD range from cognitive pro blems, such as apathy, depression, anxiety disor- ders, and hallucinations, to fatigue, gai t and balance disturbances, hypophonia, sleep disorders, sexual dysfunction, bowel problems , drenching sweats, sialorrhoea, and pain. Th ese symptoms are oft en the most troubling fo r patients, and contribute signifi cantly to mor- bidity and impaired quality of life (60, 61). Diplopia is a frequent symptom even in early PD, although the neurological basis is no t known. Pharmacological therapy in early PD is focused on oral drug treatment. Th ere are several g roups or classes of agent with proven effi cacy in PD. Levodopa Levodopa is routinely administered in combination with a periph- eral decarboxylas e inhibitor to prevent its peripheral metabolism to dopamine and the development of nausea and vomiting due to acti- vation of dopamine receptors in the area postrema which are not p rotected by the blood \200\223brain barrier. Levodopa remains the most eff ective symptomat ic oral treatment for PD, and the gold standard against which new therapies are compared. A lmost all PD patients experience improvement, and failure to respond to an adequate trial s hould cause the diagnosis to be questioned. Levodopa benefi ts the classic motor features o f PD, increases independence, prolongs employability, improves quality of life, and enhance s lifespan (75). However, there are important limitations on levodopa therapy. Acute side e ff ects include nausea, vomiting, and orthostatic hypo- tension, but if they occur are usua lly transient and can usually be avoided by gradual titration. Motor complications (motor f l uctua- tions and dyskinesia) develop in the majority of patients treated for more than fi ve years, and can be disabling in some patients. Abnormalities of sleep are common in PD and are the result of a combination of the natural consequences of ageing, the underlying disease pathology (62), motor and non-motor complica tions (63, 64), and drugs (65, 66). Disordered sleep oft en results in excessive daytime sl eepiness (EDS), and this in turn may be compounded by the sedative eff ect of dopaminergic drugs (65, 66). EDS and invol- untary dozing aff ect up to 50% of PD patients, and may be p reclini- cal markers (67). In some patients, EDS has been linked with the development of su dden onset of sleep and a pattern reminiscent of narcolepsy with an abnormal sleep latency period (<5 min) in 30% of PD patients. Polysomnographic studies have showed transi- tion fr om wakefulness to sleep stage 2 within seconds without the sudden onset of REM sleep (68, 6 9). Following reports of road traf- fi c accidents caused by \200\230sudden irresistible a ttacks of sleep \200\231 in PD patients, a large body of research focused on the possible e ff ects of dopaminergic drugs and disease progression and the occurrence of sudden onset of sleep (65, 69 \200\22371). Th e issue remains unclear, although EDS is now regarded as par t of the non-motor complex of the disease progression in PD (72). Levodopa-induced motor complications consist of fl uctuations in motor response and involun tary movements known as dyskinesias. When patients initially take levodopa, the benefi ts a re long-lasting (many hours) even though the drug has a short pharmacological half-life (60 \200\22390 min). However, with continued treatment the dura- tion of benefi t following an individual dose of levodopa becomes progressively shorter until it approaches the half-lif e of the drug. Th is is known as the wearing-off eff ect. At the same time, or subse- quent ly, many patients develop dyskinesias. Th ese tend to occur at Sexual and bladder dysfunction are common and occur in both sexes. Th e dopaminergic treatm ent of PD may lead to increased sex drive, but the eff ects of the disease oft en result in impaired sex- ual performance (73). Bladder abnormalities in particular cause Oxford Textbook of Movement Disorders 78 the time of maximum levodopa benefi t and plasma concentration (peak-dose dyskinesia). Th e y are usually choreiform in nature, but can manifest as dystonia, myoclonus, or other movem ent disorders. Th ey are usually mild, but can limit the ability to fully utilize levo- dop a to control PD features. In more advanced states the dyskine- sias can be disabling, and p atients may cycle between ON periods complicated by severe dyskinesias and OFF periods in w hich they suff er severe parkinsonism. have been demonstrated to reduce both OFF time and dyskinesia in advanced patients. Acute side eff ects of dopamine agonists include nausea, vom- iting, and orthostatic hypote nsion. As with levodopa, these can usually be avoided by slow titration. Hallucinations and cognitive impairment are more common, particularly in the elderly with dopamine agonists m ore than levodopa. Sedation is a dose-related side eff ect of dopamine agonists, and sudden unintended episodes of falling asleep while driving have been reported. Patients should be informed about this potential problem and advised not to drive when tired. More recently, it has become evident that dopamine agonists are associated with a variety of impulse contr ol disorders, including pathological gambling, hypersexuality, and compulsive eating, and s hopping. Th e precise cause of levodopa-induced motor complications is not known. However, the risk of dyskinesias is increased with the dose of levodopa; doses greater than 400 mg/day are as sociated with a signifi cant risk for dyskinesia. Young patients are likewise at greater ri sk. Th e intermittent or pulsatile stimulation of dopamine receptors by levodopa causes mol ecular changes in striatal neurons, neurophysiological changes in pallidal neurons, and ult imately motor complications. It has been hypothesized that more continu- ous delivery of le vodopa might prevent the development of motor complications. MAO-B inhibitors Inhibitors of monoamine oxidase type B (MAO-B) block central dopamine meta bolism and increase synaptic concentrations of the neurotransmitter. Selegiline and rasagil ine are both relatively selective irreversible inhibitors of the MAO-B enzyme. Clinically, MAO-B inhibitors provide modest anti-parkinsonian benefi ts when used as monotherapy in ear ly disease, and reduce OFF time when used as an adjunct to levodopa in patients with motor fl uc- tuations. MAO-B inhibitors have the potential to block the oxida- tive metabolism of dopamine and thereby prevent oxidative stress. In addition, both selegiline and rasagiline incorporate a propargyl ring within their molecular structure which provides powerful anti -apoptotic eff ects in laboratory models. Th e DATATOP study showed that selegiline signifi cantly delays the time until the emer- gence of disability necessitating the introduction of levodopa in early PD patients. However, it could not be determined whether this eff ect was due to a neuroprotective eff ect that slowed disease progression, or was merely a sympt omatic eff ect that masked ongoing neurodegeneration. More recently, the ADAGIO study demon strated that early treatment with rasagiline 1 mg/day pro- vided benefi ts that could not b e achieved with delayed treatment with the same drug. Positive results in this delayed-star t study are consistent with the drug having a disease-modifying eff ect. However, the long- term clinical signifi cance of this fi nding remains to be determined (78). Because of the risk of motor complications some physicians delay the introduction of levodo pa and prefer to use alternative therapies in the early phases of the disease (see below). On the other hand, levodopa is the most eff ective therapy for PD and should not be withhel d when satisfactory control cannot otherwise be achieved. Behavioral alterations can be enc ountered in levodopa-treated patients. A dopamine dysregulation syndrome has been described where patients have a craving for levodopa and take frequent and unnecessary doses of the drug in an addictive manner. PD patients taking high doses of levodopa may also have purpos eless and stereotyped behaviors such as the meaningless assembly and dis- assembly or colle ction and sorting of objects, known as punding. Hypersexuality and other impulse control di sorders are occasion- ally encountered with levodopa, although these are more com- monly se en in conjunction with dopamine agonists. Dopamine agonists Dopamine agonists are a diverse group of chemical agents which act direct ly on the dopamine receptor. Unlike levodopa, they do not require metabolism to an active p roduct and do not undergo oxidative metabolism. Initial dopamine agonists were ergot deriva - tives (e.g. bromocriptine, pergolide, cabergoline), but these have been shown to be assoc iated with ergot-related side eff ects, includ- ing cardiac valvular damage (76), and have largely been withdrawn from the market and replaced by second-generation non-ergot dopamine agonists (e.g. pramipexole, ropinirole, rotigotine). Dopamine agonists were initially intr oduced as adjuncts to levo- dopa to improve motor function and reduce OFF time in fl uctuat ing patients. Subsequently, it was shown that initiation of PD therapy with a long-acting d opamine agonist was less likely than levodopa to induce dyskinesia. For this reason many ph ysicians initiate PD therapy with a dopamine agonist, although supplemental levodopa is eve ntually required. Maintenance of the agonist therapy in com- bination with levodopa helps t o keep the dose of the latter low and diminish the risk for subsequent dyskinesias. MAO-B inhibitors are generally safe and well-tolerated. Th ey may increase dyskinesia in le vodopa-treated patients, but this can usually be controlled by down-titrating levodopa. Sel egiline is metabolized to form an amphetamine which can cause insomnia, but this can be avo ided by administering the drug before noon. Th ere are theoretical risks of a serotonin rea ction in patients on selective serotonin-reuptake inhibitors (SSRIs), but again these are r arely encountered. COMT inhibitors When levodopa is administered in conjunction with a decarboxylase inhibitor , it is primarily metabolized by catechol- O -methyltransferase (COMT). Inhibitors of COMT increase the elimination half-life of levodopa and enhance its brain availability. Combinin g levodopa with a COMT inhibitor has been shown to reduce OFF time and to prolong ON time i n fl uctuating patients, while enhancing motor scores. Two COMT inhibitors (tolcapone and e ntacapone) have been approved, and a combination tablet of levodopa, carbidopa, and entacap one (Stalevo ) is available. Both ropinirole and pramipexole are available as once-daily oral formulations which combine eff ective treatment with ease of use and have confi rmed patient preference (77). Rotigot ine is a dopamine agonist that is administered as a transdermal patch and has the benefi t of once-daily administration. Dopamine agonists can also be administered by continuous subc utaneous infusion and CHAPTER 9 Parkinson \200\231s Disease: Premotor Features, Diagnosis, and Early Management 7 9 Side eff ects of COMT inhibitors are primarily dopaminergic (nausea, vomiting, increased dy skinesia) and can usually be con- trolled by down-titrating the dose of levodopa by 20 \200 \22330%. Severe diarrhea has been described with tolcapone, and to a lesser degree with ent acapone, which necessitates stopping the medication in 5 \200\22310% of individuals. Cases of fatal hepatic toxicity have been reported with tolcapone, and accordingly periodic monit oring of liver function is required. Th is problem has not been encountered with entacapone . Discoloration of urine can be seen with both COMT inhibitors because of accumulation of a metabolite, but is of no clinical concern. underlying disease state and is not confounded by symptomatic or pharmacological eff ects o f the study intervention. Some studies have had positive results consistent with the pos- sibility that the drug has disease-modifying eff ects. As described above, selegiline delayed the development of disab ility necessitat- ing levodopa in the DATATOP study, but this result could have been due to a previously unappreciated symptomatic eff ect of the drug that masked rather than protect ed against disease progres- sion. Co-enzyme Q10 is thought to enhance mitochondrial func- t ion, and reduced the rate of decline of UPDRS scores in a pilot study. However, the study w as underpowered and a symptomatic confound could not be excluded. Th e dopamine agonists ro pinirole and pramipexole have anti-apoptotic eff ects in the laboratory, and slowed the rat e of decline of a surrogate neuroimaging biomarker of dopamine function in comparison with levodopa. However, a pharmacological eff ect on the biomarker rather than true protec- tion of dopamine neurons could not be excluded. Th ere has been interest in the possibility that initiating levodopa in combination with a COMT inhibitor will increase its half-life and provide more continuous delivery, thereby re ducing the risk of motor complications. No benefi t was detected in early PD patients in th e recently completed STRIDE-PD study, and the main value of COMT inhibitors continues to be in patients who experience motor fl uctuations. To avoid the problem of a confounding symptomatic eff ect, a delayed-start design has been proposed. Th is is a two-period study in which subjects are randomized to receive the activ e drug or placebo in the fi rst period, while subjects in both groups receive the active dr ug in the second period. Benefi ts of the active drug at the end of period one could be due to symptomatic and/or disease-modifying eff ects. However, benefi ts of early treatment at the end of the sec- ond period, when both groups are receiving the same medication, is unl ikely to be due to a symptomatic eff ect alone and is consistent with disease modifi cation . Th is is substantiated by demonstrating that the rates of decline of motor scores in the early and delayed start groups are not converging, indicating that the benefi t of early tr eatment is enduring. In the ADAGIO study, rasagiline 1 mg met all principal endpoints of th e delayed-start study consistent with the possibility that the drug has a disease-modifying eff ect. However, the 2 mg dose failed in this same clinical trial, and the reason for the se disparate eff ects remains to be clarifi ed. Other medical therapies Centrally acting anticholinergic drugs, such as trihexyphenidyl and benztropine, were used historically for the treatment for PD but lost favor with the intro duction of dopaminergic agents. Th eir major clinical benefi t is an eff ect on tremor, alt hough it is not cer- tain that this is superior to that which is obtained with other agents such as levodopa and dopamine agonists. Still, they can be helpful in individual patients. Th eir use is limited, particularly in the eld- erly, by their propensity to induce a vari ety of side eff ects including prostatism, glaucoma, and particularly cognitive impairment. Amantadine has antiparkinsonian eff ects thought to be due to NMDA receptor antagonism. Whi le some physicians use amanta- dine in patients with early disease for its mild symptomatic eff ects, it is most widely used as an anti-dyskinesia agent in patients with advanced PD. Indeed, it is the only oral agent that has been dem- onstrated in controlled studies to re duce dyskinesia while improv- ing parkinsonian features, and this eff ect can be sustained in many patients. Side eff ects include livedo reticularis, weight gain, and, most importan tly, dose-related impairment in cognitive function. Amantadine should always be discontinue d gradually as patients can experience withdrawal symptoms. Th e importance of the delayed-start design is its potential to detect benefi ts of a putat ive neuroprotective agent that are not due to an early symptomatic eff ect and therefore mu st be due to disease modifi cation. However, long-term studies are required to deter- mine the clinical signifi cance of the drug and assess its eff ect on cumulative disability. Management of early PD Th e management of PD should be tailored to the needs of the individ ual patient, and there is no single approach that is univer- sally accepted (79, 80). Clear ly, if an agent was demonstrated to have disease-modifying eff ects it would be initiated a t the time of diagnosis. Several studies now suggest that it may be best to initi- ate symp tomatic therapy early aft er diagnosis in order to main- tain quality of life and to preser ve compensatory mechanisms and provide benefi ts even in early disease. Levodopa remains th e most eff ective symptomatic therapy for PD, and some recommend start- ing therapy early b ut with relatively low doses to minimize the risk of motor complications. Alternatively, ma ny physicians select an alternative strategy in early patients, especially if they are youn ger, in order to reduce the risk of motor complications. A compromise is to begin with an M AO-B inhibitor or a dopamine agonist and reserve levodopa for when these drugs can no longe r provide sat- isfactory control. In patients with more severe disability, in the eld- erly , where there is cognitive impairment, or where the diagnosis is Neuroprotection Despite the many therapeutic agents available for the treatment of PD, pati ents still experience intolerable disability due to dis- ease progression and the emergence of features such as falling and dementia that are not controlled with dopaminergic therapi es. Th e development of a therapy that slows or stops disease progression is the most impor tant need in PD therapeutics. Towards this end, there are many promising candidate agents b ased on targeting fac- tors implicated in the pathogenesis of PD. However, no agent which u nequivocally has a disease-modifying eff ect in PD has been deter- mined. Obstacles to defi ning a disease-modifying drug include uncertainty as to the precise cause of the disease, and exactly what to target, and a relevant animal model that refl ects the aetiopatho- gene sis of the disease in which to test promising compounds. With the identifi cation of genes and proteins associated with familial PD, it is anticipated that there will be important pr ogress in these areas in the near future. Equally challenging will be the develop- ment of an endpoint for clinical trials that provides a measure of the Oxford Textbook of Movement Disorders 80 uncertain, most physicians would elect to initiate therapy directly with levodopa. It is im portant not to deny patients levodopa in scenarios where they are not adequately controlled by alternative medications.