Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized typically by motor features of tremor, rigidity and bradykinesia, due to depletion of dopaminergic nigrostriatal neurons. PD is increasingly recognized as a non-motor disorder since symptoms such as dementia, depression and falls emerge with disease progression to become dominant in the clinical picture.Reference Hely, Morris, Reid and Trafficante1 Stern et al.Reference Stern, Lang and Poewe2 propose three phases in a new definition of PD. Phase 1 is preclinical PD, when PD-specific pathology is presumed to be present supported by imaging or putative biomarkers. Phase 2 – premotor PD – occurs when early non-motor signs due to extra nigral pathology are present. Phase 3 – motor PD – is present when classic motor signs manifest, followed by later non-motor features due to disease progression.Reference Stern, Lang and Poewe2 PD results in a significant decline in quality of lifeReference Schrag, Jahanshahi and Quinn3 for both patients and family4 and contributes to significant economic and institutional costs on family and society.Reference Stern, Lang and Poewe2
Multidisciplinary input, particularly from PD nurse specialists, should be emphasized in optimal care managementReference Jarman, Hurwitz and Cook5, Reference MacMahon and Thomas6 but is beyond the scope of this contribution. The MacMahon paradigmReference MacMahon and Thomas6 incorporates four progressive but overlapping clinical management stages (diagnosis, maintenance, complex and palliative) and provides a template for good interdisciplinary practice.Reference Iansek and Stern7
This is the first part of a two-part review and comprises an overview of pathology, aetiology and diagnosis. The second part will focus on pharmacological and surgical management and on important non-motor features.
Epidemiology
PD is uncommon before the age of 40, but affects approximately 1% of patients over the age of 60, with a rising prevalence thereafter to around 2% in the population over 80 years of age.Reference Mutch, Dingwall-Fordyce, Downie, Paterson and Roy8 There is a great variability in reported incidence rates, probably due to differences in diagnostic criteria and case ascertainment, with reported rates in Western countries ranging from 8.6 to 19.0 per 100,000 population.Reference Twelves, Perkins and Counsell9 Rates are around 1.5 times higher in men than in women although this varies across different studies.Reference Taylor, Cook and Counsell10 Western populations, Australia and Asian countries including Korea and Singapore, have a similar prevalence.Reference Mehta, Kifley, Wang, Rochtchina, Mitchell and Sue11–Reference Tan, Venketasubramanian, Jamora and Heng13 Prevalence and incidence rates in 13 African countries, however, are lower.Reference Okubadejo, Bower, Rocca and Maraganore14 There is no evidence that seasonal variation by birth date affects incidence.Reference Postuma, Wolfson, Rajput, Stoessl, Martin, Suchowersky, Chouinard, Panisset, Jog, Grimes, Marras and Lang15
Patients with PD have a reduced life expectancy compared with the general population, with an age-adjusted hazard ratio in one United States-based study of 1.6 (confidence interval 1.3–2.0).Reference Chen, Zhang, Schwarzschild, Hernan and Ascherio16
Risk factors
Many studies have confirmed an inverse association between smoking and PD. The mechanism for this remains uncertain.Reference Ritz, Ascherio, Checkoway, Marder, Nelson, Rocca, Ross, Strickland, Van Den Eeden and Gorell17 Studies on the relation between coffee and tea drinking and PD have reported inconsistent results. There is some evidence for an inverse relationship with PD.Reference Hu, Bidel, Jousilahti, Antikainen and Tuomilehto18 Higher urate levels have also been shown to be associated with a reduced risk of PD, perhaps due to the anti-oxidant properties of urate.Reference Weisskopf, O'Reilly, Chen, Schwarzschild and Ascherio19 Factors with some evidence of increased PD risk include dairy product consumption and pesticide exposure.Reference Chen, O'Reilly, McCullough, Rodriguez, Schwarzschild, Calle, Thun and Ascherio20, Reference Dick, De Palma, Ahmadi, Scott, Prescott, Bennett, Semple, Dick, Counsell, Mozzoni, Haites, Wettinger, Mutti, Otelea, Seaton, Söderkvist and Felice21
Because inflammation plays a role in the pathogenesis of PD, the relationship between NSAID use and development of PD has been examined. Results are inconsistent, with studies reporting either no effect or an inverse association with PD.Reference Ton, Heckbert, Longstreth, Rossing, Kukull, Franklin, Swanson, Smith-Weller and Checkoway22, Reference Wahner, Bronstein, Bordelon and Ritz23 There is also some evidence that the use of simvastatin is associated with a reduced incidence of PD.Reference Wahner, Bronstein, Bordelon and Ritz24
There is a higher incidence of PD in first-degree relatives of PD patients, with risk greater for siblings than for parents or children.Reference Sundquist, Li and Hemminki25 Family members have a 3- to 4-fold increased risk compared with a control population.Reference Kurz, Alves, Aarsland and Larsen26
Pathology
Neurochemistry
Depletion of dopamine is the most important neurochemical abnormality in PD. Other neurotransmitters affected include acetylcholine, serotonin and noradrenaline, but the role of these substances in the clinical syndrome is uncertain. Eighty per cent of dopamine in the brain is found in the striatonigral complex (putamen, caudate and substantia nigra), with the main source of dopamine in the complex being the substantia nigra (SN).Reference Graybiel, Hirsch and Agid27 Five dopamine receptors in two ‘families’ have been described: the D1 group (D1 and D5) and the D2 group (D2, D3 and D4). These are variably distributed in brain areas such as striatum, cortex and limbic system.
Pathophysiology of basal ganglia motor control (Figure 1)
Disruption of normal dopaminergic output from the substantia nigra interferes with the basal ganglia motor circuit. This circuit is involved in the facilitation of both voluntary and involuntary movement. The connections within the motor circuit are complex and not fully understood.Reference Wichmann, Watts and Koller28
Striatonigral dopaminergic projections connect into the circuit via both a direct and an indirect pathway. The direct pathway involves D1 receptors and acts to reduce the inhibitory output from the globus pallidus interna (GPi), mediated by γ-aminobutyric acid (GABA). The indirect pathway involves D2 receptors. This pathway acts via the globus pallidus externa and the subthalamic nucleus, again to reduce inhibitory output from the GPi.Reference Gerfen, Engber, Mahan, Suzel, Chase, Monsma and Sibley29 In Parkinson's disease, the ‘brake’ on the GPi is diminished, resulting in increased inhibitory output into the thalamocortical motor circuit.
Lewy bodies
Until recently the pathological hallmark of PD was considered to be the Lewy body. Autosomal recessive forms of PD have been described that do not exhibit Lewy body pathology (see below), but Lewy bodies are present in the more common sporadic form of PD as well as other autosomal dominant forms. Lewy bodies are also found as the defining pathology in dementia with Lewy bodies. In addition, Lewy bodies are found variably in a number of other neurodegenerative diseases, including progressive supranuclear palsy, corticobasal degeneration and motor neurone disease.Reference Gibb and Lees30 They are intra-cytoplasmic inclusion bodies consisting of an amorphous core surrounded by a less dense ‘halo’.Reference Gibb, Lees, Marsden and Fahn31 They contain a number of elements including ubiquitin, α-synuclein and proteases.Reference Lennox, Lowe and Quinn32, Reference Spillantini, Crowther, Jakes, Hasegawa and Goedert33 Their biological function is thought to involve the disposal of abnormal or damaged proteinsReference Lowe and Calne34, Reference Jellinger35 through the ubiquitin-protease system. It remains unknown whether Lewy bodies are harmful or protective in PD.Reference Harrower, Michell and Barker36
Distribution of pathology
The pathological changes in PD are widespread. Areas involved include thalamus, hypothalamus, limbic cortex, neocortex, locus coeruleus, raphe nucleus, nucleus basalis of Meynert and autonomic nervous system.Reference Gibb, Lees, Marsden and Fahn31–Reference Gibb37 The most important area affected is the substantia nigra pars compacta and it is damage here that is responsible for most of the clinical motor syndrome. It has been thought that cell loss in excess of 50% is required for symptoms to develop.Reference Fearnley and Lees38 This concept has recently been challenged; it has been suggested that, at symptom onset, only around 30% of dopaminergic SN neurones but 50–60% of their axons have been lost.Reference Cheng, Ulane and Burke39 The clinical correlates of pathology in other areas are poorly understood, but cholinergic deficit in the nucleus basalis of Meynert is increasingly implicated in impairments of memory and cognitive function.Reference Sagar and Stern40
The substantia nigra pars compacta can be further subdivided into ventral and dorsal tiers. The cells of the dorsal tier are more heavily pigmented, with neuromelanin representing higher dopamine turnover.Reference Gibb41 It is these cells that are lost preferentially in normal ageing. In contrast, the paler cells in the ventral tier are affected primarily in PD.Reference Gibb and Lees42 This argues against PD being an exaggeration of normal ageing. There is no clear evidence that the rate of progression of pathology is influenced by age of onset of PD.Reference Gibb, Lees, Marsden and Fahn31
Pathological studies have suggested that the pathology of PD may begin in the brainstem and progresses in an ascending course, towards the cortex.Reference Braak, Del Tredici, Rub, de Vos, Jansen Steur and Braak43 The dorsal motor nucleus and olfactory bulb are initially involved (Braak stage 1), with progression thereafter through the pons and medulla (stage 2). By stages 3 and 4, the pathology has advanced to the stage where clinical symptoms emerge in response to nigro-striatal cell loss and clinical diagnosis becomes possible. By stages 5 and 6, neocortical areas are affected and this is associated with the late development of cognitive problems including dementia.Reference Braak, Rub, Jansen Steur, Del Tredici and de Vos44 Lewy body pathology can be more widespread than previously recognized. It can also be found in the spinal cord, the autonomic and peripheral nervous system, the skin, retina, submandibular gland, the cardiac nervous system and other organs.Reference Djaldetti, Lev and Melamed45
Incidental Lewy body pathology
Lewy bodies can be demonstrated at post-mortem in a distribution consistent with a pathological diagnosis of PD in subjects who had shown no evidence of the clinical syndrome in life. This is known as incidental Lewy body disease (ILBD). ILBD has been regarded as preclinical PD.Reference Dickson, Fujishiro, DelleDonne, Menke, Ahmed, Klos, Josephs, Frigerio, Burnett, Parisi and Ahlskog46 The presence of other features, including the presence of low levels of reduced glutathione (see below), is consistent with this interpretation. The prevalence of ILBD varies from 1% in the fifth decade to 10% in the eighth decade.Reference Gibb and Lees30 This would suggest a preclinical course of as long as 30 years. Evidence from other sources such as PET scan studies suggest a shorter preclinical course of 5–10 years.Reference Morrish, Sawle and Brooks47
Dementia with Lewy bodies
Dementia with Lewy bodies (DLB) is the preferred term for the condition previously variously known as Lewy body dementia, senile dementia of Lewy body type, diffuse Lewy body disease and Lewy body variant of Alzheimer's disease.Reference McKeith, Galasko, Kosaka, Perry, Dickson, Hansen, Salmon, Lowe, Mirra, Byrne, Lennox, Quinn, Edwardson, Ince, Bergeron, Burns, Miller, Lovestone, Collerton, Jansen, Ballard, de Vos, Wilcock, Jellinger and Perry48 DLB is thought, by some, to be the second commonest form of dementia after Alzheimer's disease.Reference Lennox, Lowe and Quinn32–Reference McKeith, Mintzer, Aarsland, Burn, Chiu, Cohen-Mansfield, Dickson, Dubois, Duda, Feldman, Gauthier, Halliday, Lawlor, Lippa, Lopez, Carlos Machado, O'Brien, Playfer and Reid49
Clinically, the condition is characterized by fluctuating confusion, visual hallucinations, extrapyramidal features and neuroleptic sensitivity. Pathologically, Lewy bodies are found in the cortex, but in a distribution and number overlapping that present in PD. In addition, subcortical (including substantia nigra) Lewy bodies are invariably present. It is likely that DLB lies on a continuum with PD, with the separation between the two conditions largely semantic. DLB is arbitrarily categorized as dementia predominating in the first year of symptoms.Reference McKeith, Mintzer, Aarsland, Burn, Chiu, Cohen-Mansfield, Dickson, Dubois, Duda, Feldman, Gauthier, Halliday, Lawlor, Lippa, Lopez, Carlos Machado, O'Brien, Playfer and Reid49
Overlap pathologies
Considerable pathological overlap exists between synucleinopathies (such as PD, dementia with Lewy bodies and multiple system atrophy) and tauopathies (such as Alzheimer's disease). It is thought that α-synuclein may induce intracellular tau aggregation.Reference Waxman and Giasson50 Interaction of α-synuclein, tau and β-amyloid may be the mechanism of overlapping pathology between Lewy body diseases and Alzheimer's disease. These diseases may represent different points on a complex continuum of pathology.Reference Mandal, Pettegrew, Masliah, Hamilton and Mandal51
Aetiology
Genetics
Genetic studies are hampered by the lack of a biological marker for the condition. Ascertainment of affected relatives is difficult as the disease may not become apparent until many years later. Another problem is atypical presentation of the condition; for example, isolated postural tremor has been recognized as a forme fruste of PD.
Most PD patients do not have a family history of the disease, but this can be found in 20–30% of cases.Reference Veldman, Wijn, Knoers, Praamstra and Horstink52 This figure increases to 43% if a history of isolated tremor is included.Reference Bonifati, Fabrizio, Vanacore, De Mari and Meco53 In case control studies, the relative risk for a first-degree relative of an affected patient of developing PD is about 3.5.Reference Wood and Quinn54
Early twin studies failed to show an increased concordance for PD in monozygotic versus dizygotic twins. This was interpreted as evidence against a significant genetic component. Identification of affected co-twins, however, depended on the presence of overt clinical disease and was therefore poorly sensitive. A study using PET scanning to detect abnormalities of dopaminergic activity has shown a concordance rate of 75% in monozygotic twins versus 22% in dizygotic twins.Reference Piccini, Burn, Ceravolo, Maraganore and Brooks55
A study from Sweden, however, demonstrated very low concordance rates in twins.Reference Wirdefeldt, Gatz, Schalling and Pedersen56 It is possible therefore, that heritability is higher for nigrostriatal dysfunction (as demonstrated by PET), but that the subsequent development of symptomatic PD depends on an environmental insult.
A complex interaction of many genes is almost certainly involved in the majority of cases of PD, but single gene defects have been identified in some cases of familial PD. These discoveries are of great potential in helping to understand the pathophysiology of the condition. In recent years genome-wide association analyses have identified a number of low-risk susceptibility variants for Parkinson's disease, notably at the SNCA, MAPT and LRRK-2 loci.Reference Zimprich57
Single gene defects
The first single gene cause for PD was found in an Italian-American family in which parkinsonism was inherited as an autosomal dominant condition.Reference Golbe, Di Lorio, Bonavita, Miller and Duvoisin58 The disease is clinically consistent with sporadic PD, although of younger onset than is typical, and is responsive to levodopa. Lewy bodies are found at post-mortem. The cause of the syndrome in this family has been found to be a mutation of the α-synuclein gene in chromosome 4.Reference Polymeropoulos, Lavedan, Leroy, Ide, Dehejia, Dutra, Pike, Root, Rubenstein, Boyer, Stenroos, Chandrasekharappa, Athanassiadou, Papapetropoulos, Johnson, Lazzarini, Duvoisin, Di Iorio, Golbe and Nussbaum59 A number of genes for Parkinson's disease have now been reported. Where known, the protein products of these genes have been showed variously to be associated with abnormal protein accumulation and degradation, oxidative stress and mitochondrial dysfunction. Autosomal recessive forms are usually of younger onset, slower progression and without Lewy body pathology. Parkin and PINK1 have been shown to be involved in mitochondrial quality control.Reference Zimprich57 Of the dominant forms, the recently described PARK 8 is a mutation of the LRRK-2 gene, which codes for a protein named dardarin.Reference Zimprich, Biskup, Leitner, Lichtner, Farrer, Lincoln, Kachergus, Hulihan, Uitti, Calne, Stoessl, Pfeiffer, Patenge, Carbajal, Vieregge, Asmus, Müller-Myhsok, Dickson, Meitinger, Strom, Wszolek and Gasser60, Reference Paisán-Ruíz, Jain, Evans, Gilks, Simón, van der Brug, López de Munain, Aparicio, Gil, Khan, Johnson, Martinez, Nicholl, Carrera, Pena, de Silva, Lees, Martí-Massó, Pérez-Tur, Wood and Singleton61 It most closely resembles sporadic PD in age of onset and clinical features and appears to be the most common cause of autosomal-dominant PD yet discovered, with a frequency of 1% in sporadic cases and 4% in hereditary parkinsonism.Reference Gilks, Abou-Sleiman, Gandhi, Jain, Singleton, Lees, Shaw, Bhatia, Bonifati, Quinn, Lynch, Healy, Holton, Revesz and Wood62, Reference Healy, Falchi, O'Sullivan, Bonifati, Durr, Bressman, Brice, Aasly, Zabetian, Goldwurm, Ferreira, Tolosa, Kay, Klein, Williams, Marras, Lang, Wszolek, Berciano, Schapira, Lynch, Bhatia, Gasser, Lees and Wood63
Pathophysiology
The cause of PD is unknown but research has implicated the roles of oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity as potentially important mechanisms in pathophysiology. The effects of these problems may result in cell loss through apoptosis.
Oxidative stress
The presence of iron and dopamine in the substantia nigra makes the cells vulnerable to oxidative stress.Reference Marsden and Olanow64, Reference Schapira and Quinn65 Dopamine metabolism results in the generation of toxic free radicals, a process accelerated by the presence of ferrous iron. A number of cellular defence mechanisms, including the enzymes catalase and peroxidase exist, but are thought to be impaired in PD. Of particular importance in this defence is the presence of reduced glutathione. Levels of this chemical have been shown to be low in PD. Evidence for oxidative damage in the substantia nigra in PD includes increased levels of malondialdehyde, a marker of lipid peroxidation,Reference Dexter, Carter, Wells, Javoy-Agid, Agid, Lees, Jenner and Marsden66 and of 8-hydroxy-2-deoxyguanosine, indicating oxidative damage of DNA.Reference Sanchez-Ramos, Överick and Ames67
Mitochondrial dysfunction
Mitochondria are a vital element in cellular energy production. An important finding in PD is a deficiency of Complex 1 of the mitochondrial respiratory chain.Reference Schapira and Quinn65 This abnormality is specific to PD and is not found in other neurodegenerative disorders.Reference Marsden and Olanow64 Mitochondrial dysfunction may play an important role in provoking apoptotic cell death via the release of apoptotic initiating factors. Mitochondrial dysfunction can also increase oxidative stress. In addition, it has been noted that degradation of proteins by the ubiquitin-proteosome system requires a series of ATP-dependent peptidases. A mitochondrial respiratory chain defect will therefore impair this process.Reference Schapira68
Inflammation
Inflammatory processes have also been implicated in the pathophysiology of PD with increased levels of inflammatory mediators (interleukins and TNF-α) found.Reference Hong69 These stimulate the activation of microglial cells and increase nitric oxide (NO) production. This further increases oxidative stress and exacerbates cellular damage.
Excitotoxicity
Excessive glutaminergic stimulation acting on N-methyl-D-aspartate (NMDA) receptors can damage cells via activation of a number of enzyme systems.Reference Ahlskog, LeWitt and Oertel70 Stimulation is mediated by calcium ion influx. Excessive influx is prevented by maintenance of a normal membrane potential. This, in turn, relies on mitochondrial ATP production and may be deficient in PD. Physiological levels of glutamate may therefore be toxic in PD.
α-Synuclein
It has recently been suggested that pathology may be spread by a prion-like mechanism involving the transmission of conformationally altered α-synuclein.Reference Angot, Steiner, Hansen, Li and Brundin71
Diagnosis
An accurate diagnosis of PD is important for determining prognosis and validating appropriate therapy, since dopaminergic therapy is commonly associated with neuropsychiatric side-effects in the elderly, particularly confusion and hallucinosis.Reference Weintraub and Stern72 A correct diagnosis also underpins therapeutic and epidemiological research. Unfortunately, there is as yet no robust biological marker for PD despite advancing clinical research.Reference Wu, Weidong and Jankovic73
Diagnosis remains clinical, based on the core features of tremor, rigidity and bradykinesia.Reference Tolosa, Wenning and Poewe74 The latter feature is required for the definite diagnosis of parkinsonism, but may be difficult to distinguish from age-related slowingReference Rajput, Watts and Koller75 and confounders of diagnosis in the elderly such as arthritis and cerebrovascular disease.
Subtle extrapyramidal signs (EPS) are common in the elderly. EPS of variable severity were reported in 15% of community-based subjects who were 65–74 years old, and in 52% of those over 85 years of age.Reference Bennet, Beckett, Murray, Shannon, Goetz, Pilgrim and Evans76 In contrast, clinically evident parkinsonism (two or more of the cardinal motor signs) in a similar population is lower, at around 3%.Reference Moghal, Rajput, D'Arcy and Rajput77 Parkinsonian signs may occur in association with mild cognitive impairment without evidence of overt neurological disorder,Reference Boyle, Wilson, Aggarwal, Arvanitakis, Kelly, Bienias and Bennett78 and may predict incident dementia.Reference Louis, Tang and Mayeux79 Parkinsonism occurring in the context of dementia becomes increasingly common in the ninth decade.Reference Bower, Maraganore, McDonnell and Rocca80
A precise clinical definition of PD is not established, but is generally accepted as the presence of two or more cardinal motor signs (one of which must include bradykinesia) and a consistent response to levodopa, with the development of typical levodopa-induced dyskinesia indicative of PD. Asymmetric onset and classical pill rolling tremor are strong indicators of PD, but anomalies in symmetry and unusual patterns may occur.Reference Toth, Rajput and Rajput81
While diagnosis of PD may be straightforward, there is an extensive differential diagnosis, particularly at symptom onset.Reference Macphee, Playfer and Hindle82 Clinicopathological studies suggest an error rate of approximately 25% at death, although recent studies suggest an improvement to around 10%.Reference Hughes, Daniel and Lees83 However, specialists often require to revise their diagnosis during clinical follow-up, with an 8% revision rate reported in the large DATATOP study.Reference Jankovic, Rajput, McDermott and Perl84 There is a larger error rate in the community, with one study in general practice reporting that nearly 25% of patients labelled as PD have no evidence of parkinsonism.Reference Meara, Bhowmick and Hobson85 One in 20 patients in a recent community study in the west of Scotland was misdiagnosed.Reference Newman, Breen, Patterson, Hadley, Grosset and Grosset86
Population-based studies have demonstrated that 15% of patients carrying a PD diagnosis do not fulfil strict clinical criteria, and that a further 20% of patients under clinical care have not been detected.Reference Schrag, Ben-Shlomo and Quinn87 Early referral to specialist centres for diagnosis is therefore mandatory for optimal clinical care.88, 89
The most common misdiagnoses in autopsy studies are degenerative parkinsonisms such as progressive supranuclear palsy (PSP), multisystem atrophy (MSA) or corticobasal degeneration.Reference Hughes, Daniel, Blankson and Lees90 Clinical features or ‘red flags’ suggesting alternate diagnoses include a poor response to levodopa, early falls (PSP) or co-existent dementia (dementia with Lewy bodies or Alzheimer's disease), significant or early autonomic dysfunction such as orthostatic hypotension or urinary dysfunction (MSA), abnormal eye movements (PSP), and atypical tremor with predominant gait disorder and vascular risk factors (vascular parkinsonism).Reference Quinn91 A large European study has emphasized that some forms of parkinsonism may be unclassifiableReference Katzenschlager, Cardozo, Cobo, Tolosa and Lees92 and there is increasing recognition of the expanding phenotype of many parkinsonian disorders. Recently, two distinct phenotypes of PSP have been described.Reference Williams, de Silva, Paviour, Pittman, Watt, Kilford, Holton, Revesz and Lees93 The first phenotype, occurring in around two-thirds of cases, is akin to classical PSP (early falls, supranuclear palsy and cognitive dysfunction), now called Richardson syndrome; but a second group (PSP-P) demonstrated longer survival and older age at death and were characterized by asymmetric onset, tremor and initial response to levodopa. These patients were often misdiagnosed as PD.
Clinical studies usually highlight essential tremor, vascular parkinsonism and drug-induced causes as the most frequent mimics of PD, particularly in early presentation.Reference Tolosa, Wenning and Poewe74 The spectrum of drug-induced PD now extends beyond established causes such as typical and atypical neuroleptic drugs, to include agents such as sodium valproate, lithium, amiodarone and calcium channel blockers (cinnarizine and flunarizine). While symmetry of symptoms is usual, an asymmetric presentation, indistiguishable from idiopathic PD, is well recognized.
Essential tremor (ET) is a common mimic of PD because of the increasing prevalence with age. Estimates vary widely in the literature, with rates of 0.008–22% reported. A recent meta-analysis suggests the prevalence is between 0.7 and 2.2%, rising to 4.6% in those over the age of 65 years.Reference Louis and Ferriera94 This compares with a prevalence for PD of less than 0.2% in the overall population.
The tremor of ET classically has a frequency of 6–12 Hz (faster than the 4–8 Hz tremor typically seen in PD), and is usually postural in nature, i.e. occurs when the limb is held in a fixed position against gravity, or kinetic in nature, i.e. during writing or pouring liquids.Reference Benito-Leon and Louis95 The frequency of the tremor is inversely related to age,Reference Brennan, Jurewicz, Ford, Pullman and Louis96 becoming slower in older patients and thus more into the ‘parkinsonian’ range. Tremor usually starts in the arms but spreads to involve the head/neck in 34–53% of cases.Reference Bain, Findley, Thompson, Gresty, Rothwell, Harding and Marsden97–Reference Louis, Ford and Frucht100 Isolated head tremor is rare (1–10%) and points to other diagnosesReference Louis, Ford and Frucht100 such as dystonic tremor. Cogwheeling may be felt whilst testing tone but there is no true rigidity, nor is there bradykinesia.
Duration of symptoms in ET will typically be longer than that of ‘new’ PD, and family history and exacerbating or relieving factors are important to elucidate. Many patients report a significant improvement in tremor with modest alcohol intake.
Tremor disorders with extrapyramidal signs insufficient to diagnose an established neurogenerative disorder may have to be labelled as ‘indeterminate tremor syndrome’.Reference Deuschl, Bain and Brin101 Difficulties occur particularly in patients with confounding co-morbidities such as cerebrovascular disease or when essential tremor manifests with resting tremorReference Cohen, Pullman, Jurewicz, Watner and Louis102 or where postural tremor predates fully developed PD.
Use of standard clinical criteria such as the UK PD Brain bank criteria is well established in research settings and can improve the accuracy of clinical diagnosis, with diagnostic specificity and sensitivity at death estimated at around 98 and 91%.83–103 In clinical practice, strict application of these criteria will reduce the false positive rate but may reduce sensitivity, since atypical features such as autonomic dysfunction, early dementia and falls and blepharospasm are reported in pathologically confirmed PD.Reference Hughes, Ben-Shlomo, Daniel and Lees104 The importance of clinical experience and pattern recognition in diagnostic acumen is emphasized.Reference Hughes, Daniel, Ben-Shlomo and Lees103 The recent SIGN guidelines89 emphasize the poor specificity of a clinical diagnosis of PD in the early stages. Clinicians should consider this uncertainty when giving the diagnosis and planning management.
Ancillary tests including neuroimaging may play a role in supporting clinical diagnosisReference Piccini and Whone105 but cost-effectiveness is not yet established. Structural studies are generally unnecessary in uncomplicated PD but are helpful broadly in three situations. Firstly, they are mandatory in patients with commanding gait disorder to exclude normal pressure hydrocephalus, tumour or vascular parkinsonism. Secondly, particular patterns of brain atrophy or gliosis may help to define an atypical syndrome rather than PD. Mid-brain atrophy may suggest PSP, whilst cerebellar or brainstem atrophy or gliosis is more suggestive of MSA. The revised MSA consensus criteria as supportive features in distinguishing PD from MSA-P include atrophy on conventional MRI of the putamen, middle cerebellar peduncle, pons, or cerebellum. Reduced striatal levels of glucose metabolism assessed with PET in putamen, brainstem or cerebellum are also supportive, with 80–100% sensitivity.Reference Brooks106, Reference Quattrone, Nicoletti, Messina, Fera, Condino, Pugliese, Lanza, Barone, Morgante, Zappia, Aguglia and Gallo107
Finally the presence and degree of cerebrovascular changes may indicate the contribution of vascular disease to the clinical features of parkinsonism. Vascular disease may alter the phenotype of PD in older patients. The presence of basal ganglia and/or thalamic infarcts is associated with an increased likelihood of a causal relationship.
Imaging of presynaptic dopamine transporters with beta or FP CIT SPECT scanning may help to determine whether there is underlying presynaptic dopamine depletion with a high sensitivity and specificityReference Benamer, Patterson and Grosset108 and are endorsed in recent UK guidelines. However, these techniques cannot distinguish between PD and atypical syndromes such as PSP and MSA.Reference Brooks106 SPECT scanning may also be a sensitive early diagnostic marker for presynaptic parkinsonism versus non-parkinsonian tremor disorders such as essential tremor, as well as drug-induced parkinsonism and vascular parkinsonism.Reference Marshall and Grosset109 Presynaptic cerebrovascular lesions may cause ‘punched out’ areas of poor uptake on SPECT scanning and result in an abnormal scan which differs from the pattern seen in PD. For a review of dopaminergic imaging in parkinsonism, see Kemp (2005).Reference Kemp110
Recently there has been much controversy regarding the issue of SWEDDS (scans without evidence of dopaminergic deficit). A number of clinical trials using imaging modalities, both PET and SPECT,Reference Whone, Watts, Stoessl, Davis, Reske, Nahmias, Lang, Rascol, Ribeiro, Remy, Poewe, Hauser and Brooks111, Reference Fahn, Oakes, Shoulson, Kieburtz, Rudolph, Lang, Olanow, Tanner and Marek112 identified patients initially diagnosed with PD but found to have normal imaging ranging from 4% in later disease to 15% in the early stages. Although the issue remains controversial, the use of imaging as a diagnostic tool for PD has been endorsed by guideline groups (NICE and SIGN) and these patients are generally considered to have non-PD diagnosis. The most frequent mimics with a non-tremor dominant subtype of SWEDD are neuroleptic induced, vascular parkinsonism, neoplasm or Huntington's, while common mimics with tremor dominance appear to be dystonic tremor, essential tremor, psychogenic and Fragile X tremor ataxia syndrome (FXTAS).Reference Bajaj, Birchall, Patterson, Grosset and Lees113
FXTAS is a late-onset genetic neurodegenerative disorder, predominantly affecting older males, characterized by tremor and ataxia with variable parkinsonism, progressive cognitive impairment, peripheral neuropathy and psychiatric co-morbidity. FXTAS is caused by the carriage of a premutation CGG (cytosine, guanine, guanine) repeat expansion (55–200) in the fragile X mental retardation 1 (FMR1) gene.
The importance of dystonic tremor as a possible mimic and cause of SWEDD is emphasized in a landmark paper.Reference Schneider, Edwards, Mir, Cordivari, Hooker, Dickson, Quinn and Bhatia114 This study describes a group of patients with resting arm tremor associated with dystonia and ‘soft’ extrapyramidal signs such as reduced arm swing, increased limb tone and hypomimia, carrying a diagnosis of possible PD. These patients were found to have normal SPECT imaging at initial assessment and on subsequent long-term follow-up. Pointers to the diagnosis apart from the presence of dystonia are absence of true akinesia, i.e. no fatiguing on repeated movements, a pronation supination tremor of the arm, a dystonic extension of the thumb, head tremor and absence of micrographia on writing.Reference Schneider, Edwards, Mir, Cordivari, Hooker, Dickson, Quinn and Bhatia114
Other ancillary tests such as olfactory testing, transcranial sonography, genetic testing for infrequent mimics such as Huntington's disease or spinocerebellar ataxias, and sophisticated MRI studies such as diffusion weighted MRI may be useful in discriminating PD from imitators, but require further study before they can be recommended in routine practice.Reference Tolosa, Wenning and Poewe74 Cardiac MIBG (metaiodobenzylguanidine) may help to distinguish PD from MSA by demonstrating sympathetic involvement in PD but not MSA.Reference Braune115 Acute dopaminergic challenge tests lack precision and are unhelpful in discriminating PD from atypical syndromes, particularly in early disease.Reference Bhatia, Brooks, Burn, Clarke, Grosset, MacMahon, Playfer, Schapira, Stewart and Williams116 A response to a trial of chronic levodopa therapy is helpful in supporting a diagnosis of PD, but an adequate challenge should be regarded as 1000 mg per day for at least 1 month. Some patients, particularly the elderly or those with cognitive impairment, may be unable to tolerate such doses because of significant neuropsychiatric effects or postural hypotension.
Sub-groups in PD
The clinical heterogeneity of PD, even in the early stage,Reference Lewis, Foltynie, Blackwell, Robbins, Owen and Barker117 has supported the concept of sub-groups of PD. More rapidly progressive disease is recognized in the elderly,Reference Diamond, Markham, Hoehn, McDowell and Muenter118–Reference Goetz, Tanner, Stebbins and Buchman120 often associated with early postural instability and gait difficulty, so called PIGD sub-type. Other axial features that are unresponsive to levodopa, such as freezing, dysarthria and cognitive impairment,Reference Jankovic, McDermott, Carter, Gauthier, Goetz, Golbe, Huber, Koller, Olanow and Shoulson121 may be prominent in some older patients and suggest widespread pathology outside the nigrostriatal system. Atypical parkinsonian syndromes should be considered in the differential diagnosis of such cases,Reference Rajput, Pahwa, Pahwa and Rajput122 as should overlap with other common disorders of ageing such as Alzheimer's and cerebrovascular disease.Reference Nataraj and Rajput123 Older patients may have less motor fluctuation and dyskinesia despite more rapid progression.Reference Schrag, Quinn and Ben-Shlomo124
In contrast, the sub-type of tremor dominant PD is generally associated with a younger age at onset,Reference Tanner, Kinori, Goetz, Carvey and Klawans125 a more benign clinical course and preserved mental status.Reference Zetusky, Jankovic and Pirozzolo119, Reference Goetz, Tanner, Stebbins and Buchman120–Reference Roos, Jongen and van der Velde126 Conflicting studies report that prominent tremor is associated with older age,Reference Friedman127 dementiaReference Hely, Morris, Reid, O'Sullivan, Williamson, Broe and Adena128 and to a lesser extent rapid disease progression.Reference Hely, Morris, Reid, O'Sullivan, Williamson, Broe and Adena128 Other data suggest few clinical differences between young- and old-onset PD,Reference Gibb and Lees129 although muscular stiffness and sensory symptoms may be a more common presentation in younger patients.Reference Friedman127
The variance in the literature may be partly explained by methodological differences and varying clinical populations, as well as bias in the use of retrospective study design. A recent systematic review has confirmed the cluster profiles ‘old age-at-onset and rapid disease progression’ and ‘young age-at-onset and slow disease progression’ from the majority of studies.Reference van Rooden, Heiser, Kok, Verbaan, van Hilten and Marinus130
A further analysis has suggested that PD sub-types can be largely characterized by the severity of non-dopaminergic features and motor complications and are likely explained by interactions between disease mechanisms, treatment, ageing and gender.Reference van Rooden, Colas, Martínez-Martín, Visser, Verbaan, Marinus, Chaudhuri, Kok and van Hilten131
Another recent study (PD PROMS group) has looked at the association between motor sub-types and mood. Regression models suggested an increased risk of anxiety in patients with younger age-of-onset and motor fluctuations. In contrast, depression related most strongly to axial motor symptoms.Reference Burn, Landau, Hindle, Samuel, Wilson, Hurt and Brown132
Further prospective study warrants incorporation of genetic typing and neuropathology. A recent studyReference Compta, Parkkinen, O'Sullivan, Vandrovcova, Holton, Collins, Lashley, Kallis, Williams, de Silva, Lees and Revesz133 reports that a combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease.
A quantitative assessment of Lewy pathology appears more informative than Braak α-synuclein stages. Cortical β-amyloid and age at disease onset seem to determine the rate of dementia.Reference Compta, Parkkinen, O'Sullivan, Vandrovcova, Holton, Collins, Lashley, Kallis, Williams, de Silva, Lees and Revesz133 An important clinicopathological paper demonstrates that age is inversely related to the time to development of key non-motor features or so-called ‘milestones’ in disease such as falls, dementia, visual hallucinations and need for residential care with younger patients having a longer period of ‘benign’ disease. In contrast, the advanced disease phase appears similar at all ages with a common pathological end-point and a mean end-stage disease of around five years from appearance of ‘milestones’.Reference Kempster, O'Sullivan, Holton, Revesz and Lees134
Conclusions
Greater understanding of the aetiology, genetics and pathological progression of Parkinson's disease is informing our understanding of the heterogeneity of PD in clinical practice. Nevertheless, many other conditions both neurodegenerative (e.g. MSA, PSP, Alzheimer's disease) and non-neurodegenerative (e.g. cerebrovascular disease, drug-induced parkinsonism), as well as confounding co-morbidities, occur commonly in older persons and may share similar clinical features to PD. This emphasizes the importance of regular ongoing clinical follow-up by appropriately experienced movement disorder specialists in ensuring security or revision of diagnosis and optimal management.88, 89 The contribution of collaborative working between geriatricians and neurologists in the UK (supported by the British Geriatrics Society Movement Disorder Section) in advancing care and research in frail PD patients has been acknowledged.Reference Powell135
The relentless and irreversible ‘spread’ and progression of pathological changes in PD is correlated with an increasing burden of non-motor features in PD and presents a formidable challenge to the clinician as disease progresses. The second part of this contribution will review the pharmacological and surgical management of PD during the progressive stages of PD, with a focus on the assessment and management of non-motor features.
Declaration of interests
Dr Macphee and Dr Stewart have received honoraria or travel support from Abbott, Boeringher Ingelheim, Genus, Glaxo Smith Klein, Orion, Teva Lundbeck, UCB who manufacture anti-Parkinson's drugs, and GE who manufacture an isotope for DAT scanning.