Clinical and Pathological Features of Parkinson’s Disease Susanne A. Schneider and Jose A. Obeso
Abstract Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most common neurodegenerative disorder with an approximate prevalence of 0.5–1 % among persons 65–69 years of age, rising to 1–3 % among persons 80 years of age and older. Pathologically, PD is characterized by the loss of neurons in the substantia nigra pars compacta (SNpc), and by the presence of eosinophilic protein deposits (Lewy bodies) in this region, in other aminergic nuclei and in cortical and limbic structures. Moreover, it has now been shown that pathology also involves the peripheral nervous system. Braak and colleagues suggested a thread of pathology starting from the vagal nerve to progress to the brainstem, and eventually to limbic and neocortical brain regions. This progression of pathology may account for the clinical evolution of PD toward a composite symptomatology. However, this hypothesis has been criticized by others. In this chapter, we review the clinical features of PD (motor and nonmotor) and their pathological correlates.
Keywords Parkinson’s disease Pathology Lewy bodies Spread Pathological correlate Nonmotor Motor
Braak staging
Contents 1 2 3
Introduction.............................................................................................................................. Clinical Features of PD........................................................................................................... Motor Features in PD..............................................................................................................
S. A. Schneider (&) University of Kiel, Kiel, Germany e-mail: [email protected] J. A. Obeso Department of Neurology and Neuroscience, Medical School, Clinica Universitaria and CIMA, University of Navarra and CIBERNED, Pamplona, Spain e-mail: [email protected]
Curr Topics Behav Neurosci DOI: 10.1007/7854_2014_317 Springer-Verlag Berlin Heidelberg 2014
S. A. Schneider and J. A. Obeso 4 5
Motor Complications of PD Pharmacotherapy ...................................................................... Nonmotor Features in PD ....................................................................................................... 5.1 Cognitive Dysfunction.................................................................................................... 5.2 Sleep................................................................................................................................ 5.3 Gastrointestinal Function................................................................................................ 5.4 Urinary Tract Function and Sexuality ........................................................................... 5.5 Disturbed Sense of Smell and Taste.............................................................................. 6 Differential Diagnosis ............................................................................................................. 7 Disease Progression, Survival Rate, and Causes of Death.................................................... 8 Conclusions and Perspectives ................................................................................................. References......................................................................................................................................
1 Introduction Parkinson’s disease (PD) is a neurodegenerative disorder clinically characterized by levodopa-responsive slowness (bradykinesia), rigidity, tremor, and impaired postural stability (Donaldson et al. 2012). Brain pathology shows loss of neurons in the substantia nigra pars compacta (SNpc), with the presence of eosinophilic protein deposits (Lewy bodies) in the cytoplasm, and dopamine (DA) striatal depletion. These essential pathochemical characteristics account for the cardinal features of PD. It has been estimated that typical motor features appear when at least 50 % of nigral DA neurons and 70 % of putaminal DA tissue contents have been lost (Kordower et al. 2013; Fearnley and Lees 1991). After Alzheimer’s disease, PD is the second most common neurodegenerative disorder with an approximate prevalence of 0.5–1 % among persons 65–69 years of age, rising to 1–3 % among persons 80 years of age and older. In view of the aging population, the number of PD cases are expected to increase considerably over the next years. Thus, it is calculated that the number of individuals with PD over the age of 50 years will increase in Western Europe’s five most and the world’s ten most populous nations and rise to double from about 4 million in 2005 to some 8.7–9.3 million by 2030 (Dorsey et al. 2007). PD presents sporadically, by and large, and cannot be considered a typically inherited condition. However, around 15 % of individuals with PD have a firstdegree relative also affected by PD. In recent years, several monogenic causes and genetic risk factors of PD have been identified which account for about 5 % of PD patients (Gasser 2010). Interestingly, most genes so far associated with genetic PD are related to mitochondrial function but also the lysosomes and autophagy system (Surmeier and Schumacker 2013). For example, mutations in Parkin, encoding for a mitochondrial protein, is the most common cause of early onset PD (defined by an onset age of 40 years or earlier) (Bonifati 2012). Indeed, not all patients develop PD in late adulthood, but early onset cases have been well recognized and are more likely to have a genetic cause. On the other hand, the most extensively studied PD-related autosomal dominantly inherited genes include synuclein
Clinical and Pathological Features of Parkinson’s Disease
(SNCA; which is important in PD because the alpha-synuclein protein is the main component of Lewy bodies) and glucocerebrosidase (GBA), the latter of which is also the most important risk factor for sporadic PD, increasing the risk for developing the disease up to 5–13-fold in certain ethnic groups (Sidransky and Lopez 2012; Beavan and Schapira 2013). The pathological basis of PD has received large attention in recent years. Traditional studies had focused on the SNpc and the nigrostriatal dopaminergic projection. However, the discovery that Lewy bodies are constituted, among many other proteins, by ubiquitin and alpha-synuclein aggregates have substantially modified the views of PD pathology. Thus, excellent immunostaining techniques for these two proteins currently allow recognition of Lewy bodies not only in the SNpc but also in many other regions of the central and peripheral nervous system. This has led to suggest a thread of pathology in a caudo-rostral distribution (Braak et al. 2003; Wolters and Braak 2006). Alpha-synuclein pathology supposedly progresses from the caudal brainstem and olfactory bulb (in Braak stages 1–3) to subsequently spread to limbic and neocortical brain regions (in Braak stages 4–6) (Braak et al. 2003) (Fig. 1). Involvement of the vagal nerve has been hypothesized as the first pathological correlate by Braak and colleagues, and recent studies in mice suggest that resection of the autonomic nerves stops transneuronal and retrograde axonal transport of alpha-synuclein from the enteric nervous system into the brain (Pan-Montojo et al. 2012). These recent experimental studies are keeping in with Braak et al.’s original idea that synuclein pathology might first occur in the gastrointestinal tract and then slowly move into the central nervous system. Currently, a large degree of interest, if not enthusiasm, is being put into this concept. However, it is important to call attention to the fact that many aspects of Braak’s hypothesis remain to be directly proven, and that Lewy bodies as such are not yet known to disrupt cell physiology. Indeed, whether or not Lewy bodies help neurons to resist the underlying neurodegenerative mechanisms and are therefore protective, or are causal to the disease process, ultimately killing neurons, is yet undeciphered. Accordingly, the above summarized findings should be seen as state-of-the-art thinking and researching in PD etiopathogenesis cannot be considered solid factual data.
2 Clinical Features of PD Traditionally, PD is perceived as a movement disorder; the main features being slowness of movements, tremor, and muscle rigidity affecting one body part at onset. With disease progression over the years, the motor features become more generalized, the trunk tends to bend forward, balance is impaired and walking becomes difficult (Litvan et al. 2003). These cardinal features of PD respond very well to levodopa and other dopaminergic drugs. The capacity to respond to dopaminergic drugs is another essential feature of PD albeit it is not specific, as
S. A. Schneider and J. A. Obeso
Fig. 1 Stages in the development of PD-related pathology—the Braak Hypothesis. Staging of Lewy pathology according to the Braak model. Schematic summarizing the progression of Parkinson’s disease as proposed by Braak et al. (2003). According to the Braak model, asyn deposits in specific brain regions and neuronal types giving rise to Lewy pathology in a stereotypic, temporal pattern that ascends caudo-rostrally from the lower brainstem (including the dorsal motor nucleus of the vagus nerve in the medulla then the coeruleus-subcoeruleus complex, raphe nuclei, gigantocellular reticular nucleus in the medulla a and pons) through susceptible regions of the midbrain (substantia nigra and the pedunculopontine tegmental nucleus) and forebrain (e.g., amygdala) and into the cerebral cortex (e.g., anteromedial temporal mesocortex, cingulate cortex, and later neocortical structures). It is hypothesized that the disease initiates in the periphery, gaining access to the CNS through retrograde transport along projection neurons from the gastrointestinal tract. As the disease progresses, the severity of lesions in the susceptible regions increases (Visanji et al. 2013)
any other pathological process producing lesion of the SNpc and DA depletion may equally respond in the same manner. In recent years it has become more and more clear that PD is essentially a multisystem disorder presenting with numerous nonmotor features which may be present early in the evolution but typically become more prominent and disabling after many years of disease progression (Löhle et al. 2009). The diagnosis of PD is made clinically. Diagnostic tests in vivo may support the diagnosis (for example, reduced uptake on dopaminergic SPECT/PET imaging, see below) but are mainly helpful to exclude secondary and other causes.
Clinical and Pathological Features of Parkinson’s Disease
Postmortem brain pathology can confirm the diagnosis retrospectively (Donaldson et al. 2012). In the following, we will give an overview of the main motor manifestations and some other clinical (non-motor) manifestations in PD, and a brief review of their pathophysiological basis.
3 Motor Features in PD According to the Queen Square Brain Brank Criteria, slowness of movement is a sine qua non criterion for the diagnosis of PD (Lees et al. 2009) (Tables 1, 2, 3). In this context, bradykinesia refers to slowness of repetitive movements; to be separated from absence or poverty of expected spontaneous voluntary movement including slow reaction time (akinesia) and small amplitude movements (hypokinesia). In the clinical situation, these terms are often exchangeable (Lees et al. 2009). On physical examination, such slowness of voluntary movements may be observed as reduced degree of facial expression (hypomimia) and lack of spontaneous limb or trunk movements. Repetitive movements (such as finger or foot tapping) may be slow and become progressively reduced in amplitude, as if associated with fatigue. When walking patients may demonstrate general slowness with a small stepped gait, slow turning, and reduced (asymmetric) arm swing. The latter may be associated with (unilateral) shoulder pain, which may be one of the earliest symptoms, found in 35 of 309 consecutive PD patients preceding the onset of ipsilateral signs of motor parkinsonism (Stamey et al. 2008; Truong and Wolters 2009). In later stages walking may be further impaired, by short steps, shuffling and ‘‘freezing episodes’’ (a sudden inability to move the lower extremities which may be triggered by tight, cluttered spaces or when attempting to turn) associated with a risk of falling. On other occasions patients may develop festination, a gait that becomes progressively faster while the patient bends forward and ends by falling, unless someone intercept the action. The term tremor refers to a rhythmic sinusoidal movement of a body segment. In PD, tremor typically presents at rest, i.e., upon relaxation, affecting the hands characteristically as pill rolling tremor between the thumb and index finger. Rest tremor of the hand may also be triggered when walking. On action (for example, when being asked to lift the arms to keep them outstretched) the tremor typically pauses for a few seconds, followed by re-emergence of the same tremor activity. This phenomenon is rather typical of PD (i.e., absent in other types of tremor such as essential tremor). Tremor may also affect forearms, legs, the head, or jaw. The typical frequency of PD tremor is 4–6 Hz. Both tremor and bradykinesia contribute to impaired fine motor dexterity and motor coordination which is often one of the first complaints, for example, manifesting with small, untidy handwriting (micrographia).
S. A. Schneider and J. A. Obeso Table 1 Queen Square Brain Bank criteria clinical diagnostic criteria for PD (from Litvan et al. 2003) Inclustion criteria Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions) And at least one of the following: Muscular rigidity 4–6 Hz rest tremor Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction PD Parkinson disease
Table 2 Supportive prospective positive criteria of Parkinson’s disease (from Lees et al. 2009) Unilateral onset Rest tremor present Progressive disorder Persistent asymmetry affecting predominantly the side of onset Excellent response (70–100 %) to L-dopa Severe L-dopa-induced chorea L-dopa response for 5 years or more
Clinical course of 10 years or more Hyposmia Visual hallucination
Three or more required for diagnosis of definite Parkinson’s disease
Table 3 Exclusion criteria for Parkinson’s disease (from Lees et al. 2009) Exclusion criteria for Parkinson’s disease • History of repeated strokes with stepwise progression of parkinsonian features • History of repeated head injury • History of definite encephalitis • Oculogyric crises • Neuroleptic treatment at onset of symptoms • More than one affected relative • Sustained remission • Strictly unilateral features after 3 years • Supranuclear gaze palsy • Cerebellar signs • Early severe autonomic involvement • Early severe dementia with disturbances of memory, language and praxis • Babinski sign • Presence of a cerebral tumor or communicating hydrocephalus on CT scan • Negative response to large doses of L-dopa (if malabsorption excluded) • MPTP exposure CT Computed tomography
Clinical and Pathological Features of Parkinson’s Disease
Rigidity means increased muscle tone perceived by the examiner as resistance to passive displacement of a given joint. Patients feel stiff and frequently complain of muscular pain. Based on the combination of these signs, two broad types of PD have been recognized: an akinetic-rigid and a tremor-dominant form. Pathologically, as mentioned above, motor signs are mainly attributed to loss of dopaminergic neurons in the substantia nigra. Some studies tried to correlate the clinical subtype with specific changes on brain pathology, but data are conflicting. Similarly, attempts have been made to demonstrate the degree of involvement of the nigrostriatal system as the disease progresses, thus at varying time points after diagnosis. In this regard, most reviews estimate a loss of 50–70 % of SNc dopamine neurons at the time when symptoms emerge (Kordower et al. 2013). With regard to disease progression, it has been suggested that patients with the akineticrigid subtype have a greater risk to evolve toward dementia and other nonmotor problems, as they may exhibit more severe cortical Lewy body pathology and higher Braak stages than tremor-dominant patients (Selikhova et al. 2009).
4 Motor Complications of PD Pharmacotherapy The classic motor features of PD respond very well to dopaminergic replacement therapy, i.e., dopamine agonists and levodopa. As disease progresses, higher medication doses are needed, presumably because the degree of striatal DA depletion increases. The combination of larger nigrostriatal deficit and high ([600 mg/day) levodopa doses leads to motor complications with a variety of dyskinetic movements in patients with PD, all of which are highly disabling (Thanvi et al. 2007; Ondo 2011). Choreic involuntary movements occurring as peak-time dyskinesia are the most common form. They are related to peak plasma levels of levodopa. Diphasic dyskinesias (commonly dystonic in nature) develop when plasma levodopa levels are rising or falling. Motor complications may also manifest as ‘‘off’’ state dystonia, which occur when plasma levodopa levels are low (i.e., in the early morning). These problems are currently treated with fair efficacy by using continuous delivery of levodopa (intra-duodenally) or apomorphine subcutaneously and by deep brain stimulation or restricted lesion of the globus pallidus ((GP), i.e. pallidotomy) (reviewed in Cenci et al. 2011). The incidence of levodopa-induced dyskinesia (LID) in PD ranges between 9 and 80 % depending on several factors, such as age, disease severity, levodopa dosage, and treatment duration (reviewed in Manson et al. 2012). Early onset PD patients have a higher risk of developing motor complications. The pathogenesis of LID remains incompletely understood but no doubt it is the combination of a degree of nigrostriatal denervation and the effect of levodopa that plays a major role and determines the onset of LID (Voon et al. 2009; Cenci and Lundblad 2006). A key pathogenic factor in LID is the levodopa daily dose, with a threshold around 400–500 mg (Olanow et al. 2013).
S. A. Schneider and J. A. Obeso
Pathophysiologically, choreic dyskinesias are associated with decreased neuronal firing in the globus pallidus interneus (GPi). Thus, abnormally controlled and released DA from exogenous levodopa in the striatum provokes changes mainly in the ‘‘direct’’ striato-pallidal projection leading to decreased inhibitory output from basal ganglia neurons, leading to unrestrained thalamocortical drive, and the appearance of dyskinesias (Obeso et al. 2002). However, GPi hypoactivity cannot be the sole cause of development of dyskinesias in view of the fact that pallidotomy abolishes dyskinesias (Lozano 2000), and abnormal firing patterns in basal ganglia output neurons also play a role (Obeso et al. 2002). Indeed, abnormal patterns of neuronal activity, particularly in terms of enhanced synchronization of subthalamic nucleus activity in the theta/alpha band has been associated with both ‘‘peak-dose’’ and diphasic dyskinesias (Alonso-Frech et al. 2006; Alegre et al. 2012). Generally, most severe motor complications as judged by complex ‘‘on-off’’ fluctuations and continuous and debilitating dyskinesias have virtually disappeared from the clinical scenario. This is probably due to a better and more rational use of dopaminergic drugs, the reduction in daily levodopa utilization and earlier treatment of motor complications with infusion therapies and surgery.
5 Nonmotor Features in PD 5.1 Cognitive Dysfunction Cognitive dysfunction is common in PD, in particular in advanced stages. About 75–80 % of PD patients will develop dementia after 20 years of evolution. Cognitive impairment is clinically characterized by a progressive dysexecutive syndrome with attention deficit, and short-term memory impairment (Svenningsson et al. 2012). This is often accompanied by high sensitivity to develop psychotic manifestations in response to dopaminergic drugs. It is now realized that already in earlier phase of the disease, about 25 % of nondemented PD patients suffer mild cognitive impairment (MCI), mostly in the executive domain. Clinicopathological studies demonstrated that dementia is associated with bradykinetic onset and higher cortical Lewy body burden which is combined with nondopaminergic mechanisms, i.e., cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert) (Paulus and Jellinger 1991; Bohnen and Albin 2009). Concomitant Alzheimer’s disease-like change and cerebrovascular disease have also been proposed as possible substrates of PD dementia (Pagonabarraga and Kulisevsky 2012). In fact, it has been proposed that development of dementia in PD is better explained by the coincidence of Alzheimer’s disease-like pathology and cortical Lewy bodies rather than by the presence of either of these alone (Compta et al. 2011) due to synergistic effects of amyloid, Tau, and Lewy bodies during neurodegeneration (Pagonabarraga and Kulisevsky 2012).
Clinical and Pathological Features of Parkinson’s Disease
Depression affects 30–50 % of individuals with PD, with prevalences rates of 17 % for major depression, 22 % for minor depression, and 13 % for dysthymia. Apathy has an estimated prevalence of up to 60 % in PD (Aarsland et al. 2012). Lewy body deposition in brainstem areas including in serotoninergic raphe nuclei, in the noradrenergic locus coeruleus and in cholinergic limbic pathways are proposed structures underlying depression in PD (Frisina et al. 2009; Brooks and Pavese 2011; Remy et al. 2005). Using functional imaging, function of the serotonergic system has been investigated in PD using both PET (1C-DASB to depict brain serotonin transporter availability (Politis et al. 2010); and 11C-WAY 100635 PET as a marker of serotonin 5-HT1A function) and SPECT (123I-beta-CIT) ligands. While widespread loss of brain serotonergic innervation is a feature of advanced PD (Gutteman et al. 2007), it has been proposed that serotoninergic loss may not be overly relevant to the development of depression in PD (Brooks and Pavese 2011). Using 11C-RT132 as PET tracer that binds with similar affinity to both DA and noradrenaline membrane transporters the locus coeruleus and areas of the limbic system were identified to have decreased binding and these findings are probably independent from Lewy body pathology affecting the locus coeruleus (Brooks and Pavese 2011).
5.2 Sleep Sixty to ninty eight percentage of PD patients encounter nocturnal sleep disturbances; in about 33 % of moderate to severe degree (Garcia-Borreguero et al. 2003; Diederich and McIntyre 2012). This includes nocturnal awakenings or sleep fragmentation, apnea, restless legs syndrome (RLS), periodic limb movement during sleep (PLMS), and REM sleep behavior disorder (RBD) (Raggi et al. 2013). The latter is characterized by vigorous movements during REM sleep without atonia and the occurrence of dream enactment. The RBD is present in 25–50 % of PD patients. It has been hypothesized that this may be caused by synucleinopathic involvement of the locus coeruleus, lower raphe, and/or pendunculopontine nucleus (with cholinergic denervation of the thalamus, as implicated in RBD) (Wolters 2009). The involvement of these structures early in the pathological staging may explain why many patients report of sleep abnormalities prior to motor symptom onset. Notably, presence of RBD in non-PD individuals is associated with a considerable risk of up to 80 % of developing PD or other defined neurodegenerative synucleinopathy (like dementia with Lewy bodies or multiple system atrophy (MSA)) (Postuma 2014), and patients should be monitored accordingly.
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Fig. 2 Prevalence of nonmotor symptoms (NMS) in different stages of PD. The figure is taken from the Priamo Study (Barone et al. 2009) assessing different NMS (gastrointestintal, urinary symptoms, pain, sleep disorders, skin changes etc.) in a large cohort of 1072 patients. Prevalence of NMS domains according to patient’s clinical status. Left (white) bar = drug-naive patients; middle (black) bar = patients with stable disease; right (dotted) bar = patients with PD in complicated disease phases
5.3 Gastrointestinal Function Gastrointestinal dysfunction is very common in PD (Barone et al. 2009) and may be one of the earliest manifestations, in some preceding motor symptom onset by decades (Fig. 2). It may manifest with drooling and dysphagia (Nobrega et al. 2008), delayed gastric emptying accompanied by sickness and vomiting, and lower gastrointestinal symptoms, due to a dysfunction of the enteric nervous system with impaired or loss of the peristaltic transport, manifesting with constipation (Edwards et al. 1992). Of these, constipation is seen in over 50 % of PD patients constituting the most frequent gastrointestinal problem in PD (Martinez-Martin et al. 2007). There is increasing frequency with advancing disease. Pathologically, both central and peripheral mechanisms contribute to the development of constipation (Wolters 2009). In this regard, it is interesting that numerous studies have demonstrated alpha-synuclein pathology in the enteric nervous system. Thus, biopsies of the gut have revealed Lewy bodies and Lewy neurites in the mucosa and submucosa with a rostrocaudal gradient with highest density in the esophagus compared to the rectum (Derkinderen et al. 2011; Pouclet et al. 2012). Notably, one study identified abnormalities even in samples obtained prior to the motor onset (Shannon et al. 2012) which supports the Braak hypothesis of spreading disease from the vagal nerve to the brain (see above). However, there is high variability in the methods used between these studies; and confirmation of results are needed (Schneider et al. in preparation).
Clinical and Pathological Features of Parkinson’s Disease
5.4 Urinary Tract Function and Sexuality Urinary tract dysfunction is also a common problem in PD (Barone et al. 2009; Winge and Fowler 2006) (Fig. 2), albeit not as prominent as in the related disorder of MSA. Main symptoms comprise of storage dysfunction related to an overactive bladder contractility causing daytime frequency, urinary urgency and nocturia. Such storage problems are considered mainly the result of DA deficiency-induced disinhibition and hyperactivation of the micturation reflex, localized in the pontine storage and pontine micturition center in the brainstem (Wolters 2009; Yeo et al. 2012). Sexual dysfunction in PD may be present with increased (hypersexuality) or decreased libido, or erectile dysfunction. Hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erectile dysfunction) in PD, via altered dopamine-oxytocin pathways (Yeo et al. 2012; Sakakibara et al. 2010), whereas hypersexuality occurs in the context of therapy with DA agonists (reviewed in Vilas et al. 2012).
5.5 Disturbed Sense of Smell and Taste Olfactory loss is present to some degree in 80–96 % of PD patients and often precedes motor symptom onset (Katzenschlager and Lees 2004; Doty 2012). Total anosmia, however, is rare, and some patients are not aware of the deficit until their sense of smell is formally tested. On the other hand, an intact olfaction in patients with parkinsonism few years into the disease indicates a nonidiopathic PD pathology and should prompt re-evaluation. Abnormality of taste (diminished preception/threshold, taste identification, altered taste, or burning mouth) may also be present in PD (present in about 25 % of patients) (Kim et al. 2011; Kashihara et al. 2011; Shah et al. 2009). Pathological studies demonstrated Lewy body pathology in the olfactory bulb and the primary olfactory cortex, present from early disease stages conforming to the Braak classification (Wolters 2009).
6 Differential Diagnosis As mentioned above, the diagnosis of PD is made clinically. Blood tests and other investigations mainly aim at excluding secondary causes (Berardelli et al. 2013). For example, anatomical imaging may reveal vascular parkinsonism, hydrocephalus, or structural lesions of the basal ganglia. Functional imaging includes dopamine transporter (DAT) imaging to assess the integrity of the dopaminergic system or presence of presynaptic neuronal degeneration. Striatal uptake of the ligands for DAT (FP-CIT, beta-CIT, IPT, TRODAT) correlates with disease
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severity, in particular bradykinesia and rigidity, and DAT imaging has been used as marker of progression in clinical trials. Notably, uptake is altered even from early disease phases; however, DA loss (reflected by an abnormal DAT scan) is also found in related forms of neurodegenerative parkinsonism (the so-called atypical forms of parkinsonism, e.g., MSA, supranuclear palsy, etc.). In some scenarios but not used in daily clinical routine, the use of other forms of functional imaging (such as MIBG cardiac scintigraphy) may provide further information. Blood tests help to exclude metabolic conditions (such as Wilson’s disease). In young-onset cases genetic testing can ascertain or exclude some of the known monogenic forms.
7 Disease Progression, Survival Rate, and Causes of Death Progressive neuronal loss and clinical deterioration are an inexorable process in PD. Progression of global disability in PD is attributed both to an increasing motor burden (mainly driven by poorly L-dopa-responsive motor symptoms, like postural instability, freezing of gait and falls, as well as by the evolution of levodopa-related motor complications) and to nonmotor (mainly cognitive) decline (Maetzler et al. 2009; Poewe 2009). Two general observations have been made. First, age at onset plays a pivotal role for progression. Studies suggest that the disease progresses more slowly in patients with young-onset PD, which may be due to age as the main factor because, with increasing age, these young-onset patients will more and more resemble classic older onset PD (van Rooden et al. 2010). The second observation concerns the clinical phentotype: While it is impossible to predict the progression rate on an individual basis, tremor-dominant PD tends to progress more slowly than the akinetic-rigid variant (Lewis et al. 2005; Sato et al. 2006; Selikhova et al. 2009). Akinetic-rigid PD seems to be associated with higher rates of cognitive decline and shorter survival rates. In late disease stages (with survival for 15–20 years), about half of the patients require home care nursing due to the high prevalence of dementia or other severe disability. Survival time in PD has also been assessed in several studies. The Sidney multicenter study, for example, in the recent report on 20 year follow-up data, showed that median time to death was 12.4 years (Hely et al. 2008) After 20 years of follow-up, 74 % of the original patient cohort had died. Cognitive decline with dementia and older age at onset were identified as predictors of reduced survival time. It has been suggested that mortality rates increase with disease duration: thus, the standardized mortality ratio (that is the ratio of deaths in the PD group in relation to expected deaths in the general population) increased steadily in the Sydney Study from 1.8 at 5 years to 2.3 by year 10, and 2.7 by year 15; and eventually rose to 3.1 at 20 years disease duration compared to the general population (Hely et al. 2008). Main causes of death in PD include respiratory infection or insufficiency, cardiac failure but also cancer, and other causes (Roos et al. 1996; Sato et al. 2006).
Clinical and Pathological Features of Parkinson’s Disease
8 Conclusions and Perspectives It is current understanding that the pathological basis of motor PD is a depletion of nigrostriatal axon terminals, due to neuronal loss in the SNpc (with presence of Lewy bodies in the residual neurons). Involvement of adjacent areas and increasingly wide regions accounts for both nonmotor symptoms and motor features that occur in the advanced stages of PD and respond poorly to DA replacement therapy. They may reflect the fact that not only dopaminergic but other aminergic cell groups are also affected by PD pathology. Notably though, the Braak hypothesis remains contentious, particularly because the relationship between Lewy pathology and neuronal loss is quite unclear in most regions (Halliday et al. 2012; Jellinger 2012; Burke et al. 2008) Most recently, there has been interest in possible pre-symptomatic diagnosis through investigations of noncerebral regions (such as the GI tract); but the validity of these novel approaches remains to be confirmed in future studies. Current therapy of PD remains symptomatic, but, hopefully, a better understanding of the underlying pathophysiology will lay the ground for disease-modifying treatments in the near future.
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Clinical and Pathological Features of Parkinson’s Disease report: SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Disord 18(5):467–486 Löhle M, Storch A, Reichmann H (2009) Beyond tremor and rigidity: non-motor features of Parkinson’s disease. J Neural Transm 116(11):1483–1492 Lozano AM (2000) Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine. Ann Neurol 47(1):141–146 Maetzler W, Liepelt I, Berg D (2009) Progression of Parkinson’s disease in the clinical phase: potential markers. Lancet Neurol 8(12):1158–1171 Manson A, Stirpe P, Schrag A (2012) Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis 2(3):189–198 Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, MacPhee G, Brown RG, Naidu Y, Clayton L, Abe K, Tsuboi Y, MacMahon D, Barone P, Rabey M, Bonuccelli U, Forbes A, Breen K, Tluk S, Olanow CW, Thomas S, Rye D, Hand A, Williams AJ, Ondo W, Chaudhuri KR (2007) Prevalence of nonmotor symptoms in Parkinson’s disease in an international setting; study using nonmotor symptoms questionnaire in 545 patients. Mov Disord 22(11):1623–1629 Nobrega AC, Rodrigues B, Torres AC, Scarpel RD, Neves CA, Melo A (2008) Is drooling secondary to a swallowing disorder in patients with Parkinson’s disease? Parkinsonism Relat Disord 14(3):243–245 Obeso JA, Rodríguez-Oroz MC, Rodríguez M, Arbizu J, Giménez-Amaya JM (2002) The basal ganglia and disorders of movement: pathophysiological mechanisms. News Physiol Sci 17:51–55 Olanow WC, Kieburtz K, Rascol O, Poewe W, Schapira AH, Emre M, Nissinen H, Leinonen M, Stocchi F, Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s Disease (STRIDE-PD) Investigators (2013) Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord 28(8):1064–1071 Ondo (2011) Motor complications in Parkinson’s disease. Int J Neurosci 121:37–44 Pagonabarraga J, Kulisevsky J (2012) Cognitive impairment and dementia in Parkinson’s disease. Neurobiol Dis 46(3):590–596 Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A, Said J, Marsico G, Verbavatz JM, Rodrigo-Angulo M, Gille G, Funk RH, Reichmann H (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:898 Paulus W, Jellinger K (1991) The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 50(6):743–755 Poewe W (2009) Clinical measures of progression in Parkinson’s disease. Mov Disord 24(2):S671–S676 Politis M, Wu K, Loane C, Turkheimer FE, Molloy S, Brooks DJ, Piccini P (2010) Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures. Neurology 75(21):1920–1927 Postuma RB (2014) Prodromal Parkinson’s disease–using REM sleep behavior disorder as a window. Parkinsonism Relat Disord 20(Suppl 1):S1–S4 Pouclet H, Lebouvier T, Coron E, des Varannes SB, Rouaud T, Roy M, Neunlist M, Derkinderen P (2012) A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson’s disease. Neurobiol Dis. 45(1):305–309 Raggi A, Bella R, Pennisi G, Neri W, Ferri R (2013) Sleep disorders in Parkinson’s disease: a narrative review of the literature. Rev Neurosci 24(3):279–291 Remy P, Doder M, Lees A, Turjanski N, Brooks D (2005) Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128(Pt 6):1314–1322 Roos RA, Jongen JC, van der Velde EA (1996) Clinical course of patients with idiopathic Parkinson’s disease. Mov Disord 11(3):236–242 Sakakibara R, Uchiyama T, Yamanishi T, Kishi M (2010) Genitourinary dysfunction in Parkinson’s disease. Mov Disord 25(1):2–12
S. A. Schneider and J. A. Obeso Sato K, Hatano T, Yamashiro K, Kagohashi M, Nishioka K, Izawa N et al, Juntendo Parkinson Study Group (2006) Prognosis of Parkinson’s disease: time to stage III, IV, V, and to motor fluctuations. Mov Disord 21(9):1384–1395 Schneider SA, Alexoudi A, Böttner M, et al Can we use peripheral tissue biopsies to diagnose Parkinson´s disease? A review of the literature (in preparation) Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ (2009) A clinicopathological study of subtypes in Parkinson’s disease. Brain 132:2947–2957 Shah M, Deeb J, Fernando M, Noyce A, Visentin E, Findley LJ, Hawkes CH (2009) Abnormality of taste and smell in Parkinson’s disease. Parkinsonism Relat Disord 15(3):232–237 Shannon KM, Keshavarzian A, Dodiya HB, Jakate S, Kordower JH (2012) Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases.Mov Disord 27(6):716–719 Sidransky E, Lopez G (2012) The link between the GBA gene and parkinsonism. Lancet Neurol 11(11):986–998 Stamey W, Davidson A, Jankovic J (2008) Shoulder pain: a presenting symptom of Parkinson disease. J Clin Rheumatol 14(4):253–254 Surmeier DJ, Schumacker PT (2013) Calcium, bioenergetics, and neuronal vulnerability in Parkinson’s disease. J Biol Chem 288(15):10736–10741 Svenningsson P, Westman E, Ballard C, Aarsland D (2012) Cognitive impairment in patients with Parkinson’s disease: diagnosis, biomarkers, and treatment. Lancet Neurol 11(8):697–707 Thanvi B, Lo N, Robinson T (2007) Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J 83(980):384–388 Truong DD, Wolters EC (2009) Recognition and management of Parkinson’s disease during the premotor (prodromal) phase. Expert Rev Neurother 9(6):847–857 van Rooden SM, Heiser WJ, Kok JN, Verbaan D, van Hilten JJ, Marinus J (2010) The identification of Parkinson’s disease subtypes using cluster analysis: a systematic review. Mov Disord 25(8):969–978 Vilas D, Pont-Sunyer C, Tolosa E (2012) Impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord 18(Suppl 1):S80–S84 Visanji NP, Brooks PL, Hazrati LN, Lang AE (2013) The prion hypothesis in Parkinson’s disease: braak to the future. Acta Neuropathol Commun 1(1):2 Voon V, Fernagut PO, Wickens J, Baunez C, Rodriguez M, Pavon N, Juncos JL, Obeso JA, Bezard E (2009) Chronic dopaminergic stimulation in Parkinson’s disease: from dyskinesias to impulse control disorders. Lancet Neurol 8:1140–1149 Winge K, Fowler CJ (2006) Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. Mov Disord 21(6):737–745 Wolters ECh (2009) Non-motor extranigral signs and symptoms in Parkinson’s disease. Parkinsonism Relat Disord 15(Suppl 3):S6–S12 Wolters ECh, Braak H (2006) Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl 70:309–319 Schneider SA, Alexoudi A, Boettner M, Deuschl G, Wedel T (in prep) Can we use peripheral tissue biopsies to diagnose Parkinson´s disease? A review of the literature Yeo L, Singh R, Gundeti M, Barua JM, Masood J (2012) Urinary tract dysfunction in Parkinson’s disease: a review. Int Urol Nephrol 44(2):415–424
Abstract Parkinson’s disease (PD) is, after Alzheimer’s disease, the second most common neurodegenerative disorder with an approximate prevalence of 0.5–1 % among persons 65–69 years of age, rising to 1–3 % among persons 80 years of age and older. Pathologically, PD is characterized by the loss of neurons in the substantia nigra pars compacta (SNpc), and by the presence of eosinophilic protein deposits (Lewy bodies) in this region, in other aminergic nuclei and in cortical and limbic structures. Moreover, it has now been shown that pathology also involves the peripheral nervous system. Braak and colleagues suggested a thread of pathology starting from the vagal nerve to progress to the brainstem, and eventually to limbic and neocortical brain regions. This progression of pathology may account for the clinical evolution of PD toward a composite symptomatology. However, this hypothesis has been criticized by others. In this chapter, we review the clinical features of PD (motor and nonmotor) and their pathological correlates.
Keywords Parkinson’s disease Pathology Lewy bodies Spread Pathological correlate Nonmotor Motor
Braak staging
Contents 1 2 3
Introduction.............................................................................................................................. Clinical Features of PD........................................................................................................... Motor Features in PD..............................................................................................................
S. A. Schneider (&) University of Kiel, Kiel, Germany e-mail: [email protected] J. A. Obeso Department of Neurology and Neuroscience, Medical School, Clinica Universitaria and CIMA, University of Navarra and CIBERNED, Pamplona, Spain e-mail: [email protected]
Curr Topics Behav Neurosci DOI: 10.1007/7854_2014_317 Springer-Verlag Berlin Heidelberg 2014
S. A. Schneider and J. A. Obeso 4 5
Motor Complications of PD Pharmacotherapy ...................................................................... Nonmotor Features in PD ....................................................................................................... 5.1 Cognitive Dysfunction.................................................................................................... 5.2 Sleep................................................................................................................................ 5.3 Gastrointestinal Function................................................................................................ 5.4 Urinary Tract Function and Sexuality ........................................................................... 5.5 Disturbed Sense of Smell and Taste.............................................................................. 6 Differential Diagnosis ............................................................................................................. 7 Disease Progression, Survival Rate, and Causes of Death.................................................... 8 Conclusions and Perspectives ................................................................................................. References......................................................................................................................................
1 Introduction Parkinson’s disease (PD) is a neurodegenerative disorder clinically characterized by levodopa-responsive slowness (bradykinesia), rigidity, tremor, and impaired postural stability (Donaldson et al. 2012). Brain pathology shows loss of neurons in the substantia nigra pars compacta (SNpc), with the presence of eosinophilic protein deposits (Lewy bodies) in the cytoplasm, and dopamine (DA) striatal depletion. These essential pathochemical characteristics account for the cardinal features of PD. It has been estimated that typical motor features appear when at least 50 % of nigral DA neurons and 70 % of putaminal DA tissue contents have been lost (Kordower et al. 2013; Fearnley and Lees 1991). After Alzheimer’s disease, PD is the second most common neurodegenerative disorder with an approximate prevalence of 0.5–1 % among persons 65–69 years of age, rising to 1–3 % among persons 80 years of age and older. In view of the aging population, the number of PD cases are expected to increase considerably over the next years. Thus, it is calculated that the number of individuals with PD over the age of 50 years will increase in Western Europe’s five most and the world’s ten most populous nations and rise to double from about 4 million in 2005 to some 8.7–9.3 million by 2030 (Dorsey et al. 2007). PD presents sporadically, by and large, and cannot be considered a typically inherited condition. However, around 15 % of individuals with PD have a firstdegree relative also affected by PD. In recent years, several monogenic causes and genetic risk factors of PD have been identified which account for about 5 % of PD patients (Gasser 2010). Interestingly, most genes so far associated with genetic PD are related to mitochondrial function but also the lysosomes and autophagy system (Surmeier and Schumacker 2013). For example, mutations in Parkin, encoding for a mitochondrial protein, is the most common cause of early onset PD (defined by an onset age of 40 years or earlier) (Bonifati 2012). Indeed, not all patients develop PD in late adulthood, but early onset cases have been well recognized and are more likely to have a genetic cause. On the other hand, the most extensively studied PD-related autosomal dominantly inherited genes include synuclein
Clinical and Pathological Features of Parkinson’s Disease
(SNCA; which is important in PD because the alpha-synuclein protein is the main component of Lewy bodies) and glucocerebrosidase (GBA), the latter of which is also the most important risk factor for sporadic PD, increasing the risk for developing the disease up to 5–13-fold in certain ethnic groups (Sidransky and Lopez 2012; Beavan and Schapira 2013). The pathological basis of PD has received large attention in recent years. Traditional studies had focused on the SNpc and the nigrostriatal dopaminergic projection. However, the discovery that Lewy bodies are constituted, among many other proteins, by ubiquitin and alpha-synuclein aggregates have substantially modified the views of PD pathology. Thus, excellent immunostaining techniques for these two proteins currently allow recognition of Lewy bodies not only in the SNpc but also in many other regions of the central and peripheral nervous system. This has led to suggest a thread of pathology in a caudo-rostral distribution (Braak et al. 2003; Wolters and Braak 2006). Alpha-synuclein pathology supposedly progresses from the caudal brainstem and olfactory bulb (in Braak stages 1–3) to subsequently spread to limbic and neocortical brain regions (in Braak stages 4–6) (Braak et al. 2003) (Fig. 1). Involvement of the vagal nerve has been hypothesized as the first pathological correlate by Braak and colleagues, and recent studies in mice suggest that resection of the autonomic nerves stops transneuronal and retrograde axonal transport of alpha-synuclein from the enteric nervous system into the brain (Pan-Montojo et al. 2012). These recent experimental studies are keeping in with Braak et al.’s original idea that synuclein pathology might first occur in the gastrointestinal tract and then slowly move into the central nervous system. Currently, a large degree of interest, if not enthusiasm, is being put into this concept. However, it is important to call attention to the fact that many aspects of Braak’s hypothesis remain to be directly proven, and that Lewy bodies as such are not yet known to disrupt cell physiology. Indeed, whether or not Lewy bodies help neurons to resist the underlying neurodegenerative mechanisms and are therefore protective, or are causal to the disease process, ultimately killing neurons, is yet undeciphered. Accordingly, the above summarized findings should be seen as state-of-the-art thinking and researching in PD etiopathogenesis cannot be considered solid factual data.
2 Clinical Features of PD Traditionally, PD is perceived as a movement disorder; the main features being slowness of movements, tremor, and muscle rigidity affecting one body part at onset. With disease progression over the years, the motor features become more generalized, the trunk tends to bend forward, balance is impaired and walking becomes difficult (Litvan et al. 2003). These cardinal features of PD respond very well to levodopa and other dopaminergic drugs. The capacity to respond to dopaminergic drugs is another essential feature of PD albeit it is not specific, as
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Fig. 1 Stages in the development of PD-related pathology—the Braak Hypothesis. Staging of Lewy pathology according to the Braak model. Schematic summarizing the progression of Parkinson’s disease as proposed by Braak et al. (2003). According to the Braak model, asyn deposits in specific brain regions and neuronal types giving rise to Lewy pathology in a stereotypic, temporal pattern that ascends caudo-rostrally from the lower brainstem (including the dorsal motor nucleus of the vagus nerve in the medulla then the coeruleus-subcoeruleus complex, raphe nuclei, gigantocellular reticular nucleus in the medulla a and pons) through susceptible regions of the midbrain (substantia nigra and the pedunculopontine tegmental nucleus) and forebrain (e.g., amygdala) and into the cerebral cortex (e.g., anteromedial temporal mesocortex, cingulate cortex, and later neocortical structures). It is hypothesized that the disease initiates in the periphery, gaining access to the CNS through retrograde transport along projection neurons from the gastrointestinal tract. As the disease progresses, the severity of lesions in the susceptible regions increases (Visanji et al. 2013)
any other pathological process producing lesion of the SNpc and DA depletion may equally respond in the same manner. In recent years it has become more and more clear that PD is essentially a multisystem disorder presenting with numerous nonmotor features which may be present early in the evolution but typically become more prominent and disabling after many years of disease progression (Löhle et al. 2009). The diagnosis of PD is made clinically. Diagnostic tests in vivo may support the diagnosis (for example, reduced uptake on dopaminergic SPECT/PET imaging, see below) but are mainly helpful to exclude secondary and other causes.
Clinical and Pathological Features of Parkinson’s Disease
Postmortem brain pathology can confirm the diagnosis retrospectively (Donaldson et al. 2012). In the following, we will give an overview of the main motor manifestations and some other clinical (non-motor) manifestations in PD, and a brief review of their pathophysiological basis.
3 Motor Features in PD According to the Queen Square Brain Brank Criteria, slowness of movement is a sine qua non criterion for the diagnosis of PD (Lees et al. 2009) (Tables 1, 2, 3). In this context, bradykinesia refers to slowness of repetitive movements; to be separated from absence or poverty of expected spontaneous voluntary movement including slow reaction time (akinesia) and small amplitude movements (hypokinesia). In the clinical situation, these terms are often exchangeable (Lees et al. 2009). On physical examination, such slowness of voluntary movements may be observed as reduced degree of facial expression (hypomimia) and lack of spontaneous limb or trunk movements. Repetitive movements (such as finger or foot tapping) may be slow and become progressively reduced in amplitude, as if associated with fatigue. When walking patients may demonstrate general slowness with a small stepped gait, slow turning, and reduced (asymmetric) arm swing. The latter may be associated with (unilateral) shoulder pain, which may be one of the earliest symptoms, found in 35 of 309 consecutive PD patients preceding the onset of ipsilateral signs of motor parkinsonism (Stamey et al. 2008; Truong and Wolters 2009). In later stages walking may be further impaired, by short steps, shuffling and ‘‘freezing episodes’’ (a sudden inability to move the lower extremities which may be triggered by tight, cluttered spaces or when attempting to turn) associated with a risk of falling. On other occasions patients may develop festination, a gait that becomes progressively faster while the patient bends forward and ends by falling, unless someone intercept the action. The term tremor refers to a rhythmic sinusoidal movement of a body segment. In PD, tremor typically presents at rest, i.e., upon relaxation, affecting the hands characteristically as pill rolling tremor between the thumb and index finger. Rest tremor of the hand may also be triggered when walking. On action (for example, when being asked to lift the arms to keep them outstretched) the tremor typically pauses for a few seconds, followed by re-emergence of the same tremor activity. This phenomenon is rather typical of PD (i.e., absent in other types of tremor such as essential tremor). Tremor may also affect forearms, legs, the head, or jaw. The typical frequency of PD tremor is 4–6 Hz. Both tremor and bradykinesia contribute to impaired fine motor dexterity and motor coordination which is often one of the first complaints, for example, manifesting with small, untidy handwriting (micrographia).
S. A. Schneider and J. A. Obeso Table 1 Queen Square Brain Bank criteria clinical diagnostic criteria for PD (from Litvan et al. 2003) Inclustion criteria Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions) And at least one of the following: Muscular rigidity 4–6 Hz rest tremor Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction PD Parkinson disease
Table 2 Supportive prospective positive criteria of Parkinson’s disease (from Lees et al. 2009) Unilateral onset Rest tremor present Progressive disorder Persistent asymmetry affecting predominantly the side of onset Excellent response (70–100 %) to L-dopa Severe L-dopa-induced chorea L-dopa response for 5 years or more
Clinical course of 10 years or more Hyposmia Visual hallucination
Three or more required for diagnosis of definite Parkinson’s disease
Table 3 Exclusion criteria for Parkinson’s disease (from Lees et al. 2009) Exclusion criteria for Parkinson’s disease • History of repeated strokes with stepwise progression of parkinsonian features • History of repeated head injury • History of definite encephalitis • Oculogyric crises • Neuroleptic treatment at onset of symptoms • More than one affected relative • Sustained remission • Strictly unilateral features after 3 years • Supranuclear gaze palsy • Cerebellar signs • Early severe autonomic involvement • Early severe dementia with disturbances of memory, language and praxis • Babinski sign • Presence of a cerebral tumor or communicating hydrocephalus on CT scan • Negative response to large doses of L-dopa (if malabsorption excluded) • MPTP exposure CT Computed tomography
Clinical and Pathological Features of Parkinson’s Disease
Rigidity means increased muscle tone perceived by the examiner as resistance to passive displacement of a given joint. Patients feel stiff and frequently complain of muscular pain. Based on the combination of these signs, two broad types of PD have been recognized: an akinetic-rigid and a tremor-dominant form. Pathologically, as mentioned above, motor signs are mainly attributed to loss of dopaminergic neurons in the substantia nigra. Some studies tried to correlate the clinical subtype with specific changes on brain pathology, but data are conflicting. Similarly, attempts have been made to demonstrate the degree of involvement of the nigrostriatal system as the disease progresses, thus at varying time points after diagnosis. In this regard, most reviews estimate a loss of 50–70 % of SNc dopamine neurons at the time when symptoms emerge (Kordower et al. 2013). With regard to disease progression, it has been suggested that patients with the akineticrigid subtype have a greater risk to evolve toward dementia and other nonmotor problems, as they may exhibit more severe cortical Lewy body pathology and higher Braak stages than tremor-dominant patients (Selikhova et al. 2009).
4 Motor Complications of PD Pharmacotherapy The classic motor features of PD respond very well to dopaminergic replacement therapy, i.e., dopamine agonists and levodopa. As disease progresses, higher medication doses are needed, presumably because the degree of striatal DA depletion increases. The combination of larger nigrostriatal deficit and high ([600 mg/day) levodopa doses leads to motor complications with a variety of dyskinetic movements in patients with PD, all of which are highly disabling (Thanvi et al. 2007; Ondo 2011). Choreic involuntary movements occurring as peak-time dyskinesia are the most common form. They are related to peak plasma levels of levodopa. Diphasic dyskinesias (commonly dystonic in nature) develop when plasma levodopa levels are rising or falling. Motor complications may also manifest as ‘‘off’’ state dystonia, which occur when plasma levodopa levels are low (i.e., in the early morning). These problems are currently treated with fair efficacy by using continuous delivery of levodopa (intra-duodenally) or apomorphine subcutaneously and by deep brain stimulation or restricted lesion of the globus pallidus ((GP), i.e. pallidotomy) (reviewed in Cenci et al. 2011). The incidence of levodopa-induced dyskinesia (LID) in PD ranges between 9 and 80 % depending on several factors, such as age, disease severity, levodopa dosage, and treatment duration (reviewed in Manson et al. 2012). Early onset PD patients have a higher risk of developing motor complications. The pathogenesis of LID remains incompletely understood but no doubt it is the combination of a degree of nigrostriatal denervation and the effect of levodopa that plays a major role and determines the onset of LID (Voon et al. 2009; Cenci and Lundblad 2006). A key pathogenic factor in LID is the levodopa daily dose, with a threshold around 400–500 mg (Olanow et al. 2013).
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Pathophysiologically, choreic dyskinesias are associated with decreased neuronal firing in the globus pallidus interneus (GPi). Thus, abnormally controlled and released DA from exogenous levodopa in the striatum provokes changes mainly in the ‘‘direct’’ striato-pallidal projection leading to decreased inhibitory output from basal ganglia neurons, leading to unrestrained thalamocortical drive, and the appearance of dyskinesias (Obeso et al. 2002). However, GPi hypoactivity cannot be the sole cause of development of dyskinesias in view of the fact that pallidotomy abolishes dyskinesias (Lozano 2000), and abnormal firing patterns in basal ganglia output neurons also play a role (Obeso et al. 2002). Indeed, abnormal patterns of neuronal activity, particularly in terms of enhanced synchronization of subthalamic nucleus activity in the theta/alpha band has been associated with both ‘‘peak-dose’’ and diphasic dyskinesias (Alonso-Frech et al. 2006; Alegre et al. 2012). Generally, most severe motor complications as judged by complex ‘‘on-off’’ fluctuations and continuous and debilitating dyskinesias have virtually disappeared from the clinical scenario. This is probably due to a better and more rational use of dopaminergic drugs, the reduction in daily levodopa utilization and earlier treatment of motor complications with infusion therapies and surgery.
5 Nonmotor Features in PD 5.1 Cognitive Dysfunction Cognitive dysfunction is common in PD, in particular in advanced stages. About 75–80 % of PD patients will develop dementia after 20 years of evolution. Cognitive impairment is clinically characterized by a progressive dysexecutive syndrome with attention deficit, and short-term memory impairment (Svenningsson et al. 2012). This is often accompanied by high sensitivity to develop psychotic manifestations in response to dopaminergic drugs. It is now realized that already in earlier phase of the disease, about 25 % of nondemented PD patients suffer mild cognitive impairment (MCI), mostly in the executive domain. Clinicopathological studies demonstrated that dementia is associated with bradykinetic onset and higher cortical Lewy body burden which is combined with nondopaminergic mechanisms, i.e., cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert) (Paulus and Jellinger 1991; Bohnen and Albin 2009). Concomitant Alzheimer’s disease-like change and cerebrovascular disease have also been proposed as possible substrates of PD dementia (Pagonabarraga and Kulisevsky 2012). In fact, it has been proposed that development of dementia in PD is better explained by the coincidence of Alzheimer’s disease-like pathology and cortical Lewy bodies rather than by the presence of either of these alone (Compta et al. 2011) due to synergistic effects of amyloid, Tau, and Lewy bodies during neurodegeneration (Pagonabarraga and Kulisevsky 2012).
Clinical and Pathological Features of Parkinson’s Disease
Depression affects 30–50 % of individuals with PD, with prevalences rates of 17 % for major depression, 22 % for minor depression, and 13 % for dysthymia. Apathy has an estimated prevalence of up to 60 % in PD (Aarsland et al. 2012). Lewy body deposition in brainstem areas including in serotoninergic raphe nuclei, in the noradrenergic locus coeruleus and in cholinergic limbic pathways are proposed structures underlying depression in PD (Frisina et al. 2009; Brooks and Pavese 2011; Remy et al. 2005). Using functional imaging, function of the serotonergic system has been investigated in PD using both PET (1C-DASB to depict brain serotonin transporter availability (Politis et al. 2010); and 11C-WAY 100635 PET as a marker of serotonin 5-HT1A function) and SPECT (123I-beta-CIT) ligands. While widespread loss of brain serotonergic innervation is a feature of advanced PD (Gutteman et al. 2007), it has been proposed that serotoninergic loss may not be overly relevant to the development of depression in PD (Brooks and Pavese 2011). Using 11C-RT132 as PET tracer that binds with similar affinity to both DA and noradrenaline membrane transporters the locus coeruleus and areas of the limbic system were identified to have decreased binding and these findings are probably independent from Lewy body pathology affecting the locus coeruleus (Brooks and Pavese 2011).
5.2 Sleep Sixty to ninty eight percentage of PD patients encounter nocturnal sleep disturbances; in about 33 % of moderate to severe degree (Garcia-Borreguero et al. 2003; Diederich and McIntyre 2012). This includes nocturnal awakenings or sleep fragmentation, apnea, restless legs syndrome (RLS), periodic limb movement during sleep (PLMS), and REM sleep behavior disorder (RBD) (Raggi et al. 2013). The latter is characterized by vigorous movements during REM sleep without atonia and the occurrence of dream enactment. The RBD is present in 25–50 % of PD patients. It has been hypothesized that this may be caused by synucleinopathic involvement of the locus coeruleus, lower raphe, and/or pendunculopontine nucleus (with cholinergic denervation of the thalamus, as implicated in RBD) (Wolters 2009). The involvement of these structures early in the pathological staging may explain why many patients report of sleep abnormalities prior to motor symptom onset. Notably, presence of RBD in non-PD individuals is associated with a considerable risk of up to 80 % of developing PD or other defined neurodegenerative synucleinopathy (like dementia with Lewy bodies or multiple system atrophy (MSA)) (Postuma 2014), and patients should be monitored accordingly.
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Fig. 2 Prevalence of nonmotor symptoms (NMS) in different stages of PD. The figure is taken from the Priamo Study (Barone et al. 2009) assessing different NMS (gastrointestintal, urinary symptoms, pain, sleep disorders, skin changes etc.) in a large cohort of 1072 patients. Prevalence of NMS domains according to patient’s clinical status. Left (white) bar = drug-naive patients; middle (black) bar = patients with stable disease; right (dotted) bar = patients with PD in complicated disease phases
5.3 Gastrointestinal Function Gastrointestinal dysfunction is very common in PD (Barone et al. 2009) and may be one of the earliest manifestations, in some preceding motor symptom onset by decades (Fig. 2). It may manifest with drooling and dysphagia (Nobrega et al. 2008), delayed gastric emptying accompanied by sickness and vomiting, and lower gastrointestinal symptoms, due to a dysfunction of the enteric nervous system with impaired or loss of the peristaltic transport, manifesting with constipation (Edwards et al. 1992). Of these, constipation is seen in over 50 % of PD patients constituting the most frequent gastrointestinal problem in PD (Martinez-Martin et al. 2007). There is increasing frequency with advancing disease. Pathologically, both central and peripheral mechanisms contribute to the development of constipation (Wolters 2009). In this regard, it is interesting that numerous studies have demonstrated alpha-synuclein pathology in the enteric nervous system. Thus, biopsies of the gut have revealed Lewy bodies and Lewy neurites in the mucosa and submucosa with a rostrocaudal gradient with highest density in the esophagus compared to the rectum (Derkinderen et al. 2011; Pouclet et al. 2012). Notably, one study identified abnormalities even in samples obtained prior to the motor onset (Shannon et al. 2012) which supports the Braak hypothesis of spreading disease from the vagal nerve to the brain (see above). However, there is high variability in the methods used between these studies; and confirmation of results are needed (Schneider et al. in preparation).
Clinical and Pathological Features of Parkinson’s Disease
5.4 Urinary Tract Function and Sexuality Urinary tract dysfunction is also a common problem in PD (Barone et al. 2009; Winge and Fowler 2006) (Fig. 2), albeit not as prominent as in the related disorder of MSA. Main symptoms comprise of storage dysfunction related to an overactive bladder contractility causing daytime frequency, urinary urgency and nocturia. Such storage problems are considered mainly the result of DA deficiency-induced disinhibition and hyperactivation of the micturation reflex, localized in the pontine storage and pontine micturition center in the brainstem (Wolters 2009; Yeo et al. 2012). Sexual dysfunction in PD may be present with increased (hypersexuality) or decreased libido, or erectile dysfunction. Hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erectile dysfunction) in PD, via altered dopamine-oxytocin pathways (Yeo et al. 2012; Sakakibara et al. 2010), whereas hypersexuality occurs in the context of therapy with DA agonists (reviewed in Vilas et al. 2012).
5.5 Disturbed Sense of Smell and Taste Olfactory loss is present to some degree in 80–96 % of PD patients and often precedes motor symptom onset (Katzenschlager and Lees 2004; Doty 2012). Total anosmia, however, is rare, and some patients are not aware of the deficit until their sense of smell is formally tested. On the other hand, an intact olfaction in patients with parkinsonism few years into the disease indicates a nonidiopathic PD pathology and should prompt re-evaluation. Abnormality of taste (diminished preception/threshold, taste identification, altered taste, or burning mouth) may also be present in PD (present in about 25 % of patients) (Kim et al. 2011; Kashihara et al. 2011; Shah et al. 2009). Pathological studies demonstrated Lewy body pathology in the olfactory bulb and the primary olfactory cortex, present from early disease stages conforming to the Braak classification (Wolters 2009).
6 Differential Diagnosis As mentioned above, the diagnosis of PD is made clinically. Blood tests and other investigations mainly aim at excluding secondary causes (Berardelli et al. 2013). For example, anatomical imaging may reveal vascular parkinsonism, hydrocephalus, or structural lesions of the basal ganglia. Functional imaging includes dopamine transporter (DAT) imaging to assess the integrity of the dopaminergic system or presence of presynaptic neuronal degeneration. Striatal uptake of the ligands for DAT (FP-CIT, beta-CIT, IPT, TRODAT) correlates with disease
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severity, in particular bradykinesia and rigidity, and DAT imaging has been used as marker of progression in clinical trials. Notably, uptake is altered even from early disease phases; however, DA loss (reflected by an abnormal DAT scan) is also found in related forms of neurodegenerative parkinsonism (the so-called atypical forms of parkinsonism, e.g., MSA, supranuclear palsy, etc.). In some scenarios but not used in daily clinical routine, the use of other forms of functional imaging (such as MIBG cardiac scintigraphy) may provide further information. Blood tests help to exclude metabolic conditions (such as Wilson’s disease). In young-onset cases genetic testing can ascertain or exclude some of the known monogenic forms.
7 Disease Progression, Survival Rate, and Causes of Death Progressive neuronal loss and clinical deterioration are an inexorable process in PD. Progression of global disability in PD is attributed both to an increasing motor burden (mainly driven by poorly L-dopa-responsive motor symptoms, like postural instability, freezing of gait and falls, as well as by the evolution of levodopa-related motor complications) and to nonmotor (mainly cognitive) decline (Maetzler et al. 2009; Poewe 2009). Two general observations have been made. First, age at onset plays a pivotal role for progression. Studies suggest that the disease progresses more slowly in patients with young-onset PD, which may be due to age as the main factor because, with increasing age, these young-onset patients will more and more resemble classic older onset PD (van Rooden et al. 2010). The second observation concerns the clinical phentotype: While it is impossible to predict the progression rate on an individual basis, tremor-dominant PD tends to progress more slowly than the akinetic-rigid variant (Lewis et al. 2005; Sato et al. 2006; Selikhova et al. 2009). Akinetic-rigid PD seems to be associated with higher rates of cognitive decline and shorter survival rates. In late disease stages (with survival for 15–20 years), about half of the patients require home care nursing due to the high prevalence of dementia or other severe disability. Survival time in PD has also been assessed in several studies. The Sidney multicenter study, for example, in the recent report on 20 year follow-up data, showed that median time to death was 12.4 years (Hely et al. 2008) After 20 years of follow-up, 74 % of the original patient cohort had died. Cognitive decline with dementia and older age at onset were identified as predictors of reduced survival time. It has been suggested that mortality rates increase with disease duration: thus, the standardized mortality ratio (that is the ratio of deaths in the PD group in relation to expected deaths in the general population) increased steadily in the Sydney Study from 1.8 at 5 years to 2.3 by year 10, and 2.7 by year 15; and eventually rose to 3.1 at 20 years disease duration compared to the general population (Hely et al. 2008). Main causes of death in PD include respiratory infection or insufficiency, cardiac failure but also cancer, and other causes (Roos et al. 1996; Sato et al. 2006).
Clinical and Pathological Features of Parkinson’s Disease
8 Conclusions and Perspectives It is current understanding that the pathological basis of motor PD is a depletion of nigrostriatal axon terminals, due to neuronal loss in the SNpc (with presence of Lewy bodies in the residual neurons). Involvement of adjacent areas and increasingly wide regions accounts for both nonmotor symptoms and motor features that occur in the advanced stages of PD and respond poorly to DA replacement therapy. They may reflect the fact that not only dopaminergic but other aminergic cell groups are also affected by PD pathology. Notably though, the Braak hypothesis remains contentious, particularly because the relationship between Lewy pathology and neuronal loss is quite unclear in most regions (Halliday et al. 2012; Jellinger 2012; Burke et al. 2008) Most recently, there has been interest in possible pre-symptomatic diagnosis through investigations of noncerebral regions (such as the GI tract); but the validity of these novel approaches remains to be confirmed in future studies. Current therapy of PD remains symptomatic, but, hopefully, a better understanding of the underlying pathophysiology will lay the ground for disease-modifying treatments in the near future.
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