FRENKEL EXERCISE PROTOCOL PARKINSONS DISEASE

FOR

PATIENT

WITH

a)Introduction : 1. ) Definition: Parkinson's disease is a progressive, neurodegenerative disorder that affects movement, muscle control, and balance as well as numerous other functions. It is part of a group of conditions known as motor systems disorders.

2. History of Parkinsons disease: Parkinson's disease was named for James Parkinson, a general practitioner in London during the 19th century who first described the symptoms of the disease. Symptoms describing Parkinson's disease are mentioned in the writings of medicine in India dating back to 5,000 BCE as well as in Chinese writings dating back approximately 2500 years. 3. Epidemiology: PD is the second most common neurodegenerative disorder after Alzheimer's disease.[59] The prevalence (proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to 4% of the population over 80.[59] The mean age of onset is around 60 years, although 510% of cases, classified as young onset, begin between the ages of 20 and 50.[2] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[59] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.[59] The incidence of PD is between 8 and 18 per 100,000 personyears.[59] 4. Incidence/ Prevalence Rate: World :

Asia: The standardized incidence rates is 8.7 per 100000 person-years in door-to-door surveys and 6.7 to 8.3 per 100000 person-years in record-based surveys Bangladesh: b) Neuro-Anatomy of Basal ganglia : Basal ganglia

Brain: Basal ganglia

Basal ganglia labeled at top right.

The basal ganglia (or basal nuclei) are a group of nuclei of varied origin (mostlytelencephalic embryonal origin, with some diencephalic and mesencephalic elements) in thebrains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and strongly connected with the cerebral cortex, thalamus and other brain areas. The basal ganglia are associated with a variety of functions, including voluntary motor control,

procedural learning relating to routine behaviors or "habits" such as bruxism, eye movements, and cognitive,[1] emotional functions.[2] Currently popular theories implicate the basal ganglia primarily in action selection, that is, the decision of which of several possible behaviors to execute at a given time.[1][

Anatomy In terms of development, the human nervous system is often classified based on the original 3 primitive vesicles from which it develops: These primary vesicles form in the normal development of the neural tube of the human fetus and initially include prosencephalon, mesencephalon, and rhombencephalon, in rostral to caudal (from head to toe) orientation. Later in development of the nervous system each section itself turns into smaller components. The following table demonstrates this developmental classification and traces it to the anatomic structures found in the basal ganglia[1][5][7] (the structures relevant to the basal ganglia are shown in bold): Primary division of theneural tube

Secondary subdivision

Final segments in a human adult

1. The human cortex (both 1. Telencephalon Prosencephalon 2. Diencephalon 2. Thalamus, hypothalamus, subthalamus, epithalamus, subthalamic nuclei Mesencephalon 1. Mesencephalon (Midbrain), Substantia 1. Mesencephalon nigra pars compacta (SNc),Substantia nigra pars reticulata (SNr) 1. Metencephalon Rhombencephalon 2. Myelencephalon 2. Medulla 1. Pons and cerebellum hemispheres), Caudate, Putamen, Globus pallidus (pallidum)

Coronal slices of human brain showing the basal ganglia. White matter is shown in dark gray, gray matter is show in light gray. Anterior: striatum, globus pallidus (GPe and GPi) Posterior: subthalamic nucleus (STN), substantia nigra (SN) The basal ganglia form a fundamental component of thetelencephalon (forebrain). In contrast to the cortical layer that lines the surface of the forebrain, the basal ganglia are a collection of distinct masses of gray matter lying deep in the brain not far from the junction of the thalamus. Like most parts of the brain, the basal ganglia consist of left and right sides that are virtual mirror images of each other. In terms of anatomy, the basal ganglia are divided by anatomists into four distinct structures, depending on how superior or rostralthey are (in other words depending on how close to the top of the head they are): Two of them, the striatum and the pallidum, are relatively large; the other two, the substantia nigra and thesubthalamic nucleus, are smaller. In the illustration to the right, twocoronal sections of the human brain show the location of the basal ganglia components. Of note, and not seen in this section, the subthalamic nucleus and substantia nigra lie farther back (posteriorly) in the brain than the striatum and pallidum. [edit]Striatum Main article: Striatum The striatum is the largest component of the basal ganglia. The term "striatum" comes from the observation that this structure has a striped appearance when sliced in certain directions, arising from numerous large and small bundles of nerve fibers (white matter) that traverse it. Early anatomists, examining the human brain, perceived the striatum as two distinct masses of gray matter separated by a large tract of white matter called the internal capsule. They named these two masses the "caudate nucleus" and "putamen". More recent anatomists have concluded, on the basis of microscopic and neurochemical studies, that it is more appropriate to

consider these masses as two separated parts of a single entity, the "striatum", in the same way that a city may be separated into two parts by a river. Numerous functional differences between the caudate and putamen have been identified, but these are taken to be consequences of the fact that each sector of the striatum is preferentially connected to specific parts of the cerebral cortex. The internal organization of the striatum is extraordinarily complex. The great majority of neurons (about 96%) are of a type called "medium spiny neurons".[1] These are GABAergic cells (meaning that they inhibit their targets) with small cell bodies and dendrites densely covered with dendritic spines, which receive synaptic input primarily from the cortex and thalamus. Medium spiny neurons can be divided into subtypes in a number of ways, on the basis of neurochemistry and connectivity. The next most numerous type (around 2%) are a class of large cholinergic interneurons with smooth dendrites. There are also several other types of interneurons making up smaller fractions of the neural population. Numerous studies have shown that the connections between cortex and striatum are, in general, topographic; that is, each part of the cortex sends stronger input to some parts of the striatum than to others. The nature of the topography has been difficult to understand, howeverperhaps in part because the striatum is organized in three dimensions, whereas the cortex, as a layered structure, is organized in two. This dimensional discrepancy entails a great deal of distortion and discontinuity in mapping one structure to the other. It is interesting to note that the same topography applies to the striatal connections to the thalamus.[8] [edit]Pallidum Main article: Pallidum The pallidum consists of a large structure called the globus pallidus ("pale globe") together with a smaller ventral extension called the ventral pallidum. The globus pallidus appears as a single neural mass, but can be divided into two functionally distinct parts, called the internal(sometimes "medial") and external (sometimes "lateral") segments, abbreviated GPi and GPe.[1] Both segments contain primarily GABAergic neurons, which, therefore, have inhibitory effects on their targets. The two segments participate in distinct neural circuits. The external segment, or GPe, receives input mainly from the striatum, and projects to the subthalamic nucleus. The internal segment, or GPi, receives signals from the striatum via two pathways, called "direct" and "indirect". Pallidal neurons operate using a "disinhibition" principle. These neurons fire at steady high rates in the absence of input, and signals from the striatum cause them to "pause". Because pallidal neurons themselves have inhibitory effects on their

targets, the net effect of striatal input to the pallidum is a reduction of the tonic inhibition exerted by pallidal cells on their targets. [edit]Substantia nigra Main article: Substantia nigra The substantia nigra is a mesencephalic gray matter portion of the basal ganglia that is divided into SNr (reticulata) and SNc (compacta). SNr often works in unison with GPi, and the SNr-GPi complex inhibits the thalamus. Substantia nigra pars compacta (SNc) however, produces the neurotransmitter dopamine, which is very significant in maintaining balance in the striatal pathway. The circuit portion below explains the role and circuit connections of each of the components of the basal ganglia. [edit]Subthalamic nucleus Main article: Subthalamic nucleus The subthalamic nucleus is a diencephalic gray matter portion of the basal ganglia, and the only portion of the ganglia that actually produces an "excitatory," glutamate neurotransmitter. The role of the subthalamic nucleus (STN) is to stimulate the SNr-GPi complex and it is part of the "indirect pathway". [edit]Circuit connections

Connectivity diagram showing excitatory glutamatergic pathways asred, inhibitory GABAergic pathways asblue, and modulatory dopaminergicpathways as magenta. (Abbreviations: GPe: globus pallidus external; GPi: globus pallidus internal; STN: subthalamic nucleus; SNc: substantia nigra compacta; SNr: substantia nigra reticulata) In order to understand the complex circuitry of the basal ganglia, one has to first understand the important participants in this circuit. Parts of the basal ganglia are in direct communication with

the thalamus and the cortex. The cortex, thalamus, and the basal ganglia are, therefore, the three main participants in the circuit created by the basal ganglia. At the top of the hierarchy lies the cerebral cortex. The cortex has many different areas with different functions. One such cortical area is called the primary motor cortex (along the precentral gyrus). Specialized neurons from the primary motor cortex extend their axons all the way to the striatum portion of the basal ganglia. These cortical neurons release the neurotransmitter glutamate, which is excitatory in nature. Once excited by glutamate, the cells in the striatum project in two different directions giving rise to two major pathways: The "direct" and the "indirect" pathways: In the direct pathway, cortical cells project excitatory inputs to the striatum, which in turn projects inhibitory neurons onto the cells of the SNr-GPi complex. The SNr-GPi complex projects directly onto the thalamus through the inhibitory ansa lenticularis pathway. The striatal inhibition of the SNr-GPi complex coupled with SNr-GPi inhibition of the thalamus therefore results in a net reduction of inhibition of the thalamus via the striatum. The thalamus projects excitatory glutamatergic neurons to the cortex itself. The direct pathway, therefore, results in the excitation of the motor cortex by the thalamus. Once stimulated, the cortex projects its own excitatory outputs to the brain stem and ultimately muscle fibers via the lateral corticospinal tract. The following diagram depicts the direct pathway: Cortex (stimulates) Striatum (inhibits) "SNr-GPi" complex (less inhibition of thalamus) Thalamus (stimulates) Cortex (stimulates) Muscles, etc. (hyperkinetic state) The indirect pathway also starts from neurons in the striatum. Once stimulated by the cortex, striatal neurons in the indirect pathway project inhibitory axons onto the cells of the globus pallidus externa (GPe), which tonically inhibits the subthalamic nucleus (STN). This inhibition (by the striatum) of the inhibitory projections of the GPe, results in the net reduction of inhibition of the STN. The STN, in turn, projects excitatory inputs to the SNr-GPi complex (which inhibits the thalamus). The end-result is inhibition of the thalamus and, therefore, decreased stimulation of the motor cortex by the thalamus and reduced muscle activity. The direct and indirect pathways are therefore antagonist in their functions. Following is a diagram of the indirect pathway: Cortex (stimulates) Striatum (inhibits) GPe (less inhibition of STN) STN (stimulates) "SNr-GPi" complex (inhibits) Thalamus (is stimulating less) Cortex (is stimulating less) Muscles, etc. (hypokinetic state)

Main circuits of the basal ganglia. This diagram shows 2 coronal slices that have been superimposed to include the involved basal ganglia structures. The + and - signs at the point of the arrows indicate whether the pathway is excitatory or inhibitory, respectively, in effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to inhibitory GABAergicpathways and turquoise arrows refer todopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway. The antagonistic functions of the direct and indirect pathways are modulated by the substantia nigra pars compacta (SNc), which produces dopamine. Special D1-receptors in the basal ganglia are excited by dopamine, favoring the direct pathway, whereas specialized D2-receptors in the basal ganglia are inhibited in presence of dopamine and favor the indirect pathway.[1] Through these mechanisms the body is able to maintain balance between excitation and inhibition of motion. Lack of balance in this delicate system leads to pathologies such as Parkinson's disease

c) Neuro-physiology of Basal ganglia : Physiology Input signals to the striatum Signals received by the striatum from the cerebral cortex and thalamus are mediated by excitatory glutamatergic neurotransmission (Gerfen and Wilson 1996). These fast, phasically

active excitatory inputs are mediated predominantly by AMPA and kainate receptor subtypes when the medium spiny neuronal membranes are near resting potential, with NMDA receptors playing a great role when the membranes are depolarised. Glutamatergic inputs from both cerebral cortex and thalamus also impinge on striatal interneurones (Tepper and Bolam 2004, Smith et al. 1998). The effects of dopaminergic inputs on striatal neuronal activity are complicated with many conflicting results (Nicola et al. 2000). Problems undoubtedly arise because it is difficult to evoke in slice and anaesthetised prepartions the appropriately timed cortically and thalamically based inputs with which dopaminergic signals will interact (see below). However, the current weight of evidence suggests dopamine can increase signal-tonoise ratios in the striatum -- enhancing the effects of strong inputs while suppressing weak ones (Nicola et al. 2004). The actions of dopamine on GABAergic and cholinergic interneurones (Tepper and Bolam 2004, Nicola et al. 2000) may also contribute. Although anatomically significant (Soubrie et al. 1984), much less is known about the role(s) of serotoninergic inputs to the basal ganglia. Input signals to the subthalamic nucleus The main external sources of input to the striatum also provide parallel inputs to the subthalamic nucleus. The subthalamus, therefore, receives phasic excitatory glutamatergic signals both from cerebral cortex (Nambu et al. 2002) and the thalamus (Mouroux and Feger 1993). Following cortical stimulation short-latency excitatory effects in the subthalamus are thought to be mediated via these "hyperdirect" pathways while longer latency suppressive effects more likely come from indirect inhibitory inputs from other basal ganglia nuclei, principally the external globus pallidus (Nambu et al. 2002). Modulatory dopaminergic and serotoninergic inputs appear to produce local excitation in the subthalamus (Ni et al. 2001, Xiang et al. 2005). Finally, and unlike the striatum, the subthalamus is modulated by additional cholinergic signals from the tegmental pedunculopontine nucleus (Mena-Segovia et al. 2004).

Figure 5: Disinhibition is the basic process by which basal ganglia function is expressed. A schematic illustration of results reported by Chevalier and Deniau (1990) in which frequency histograms illustrate the sequence of electrophysiological events underlying the disinhibtory process. Activity was evoked in the striatum by a local injection of glutamate (arrows). The inhibitory striatonigral projection consequently induced a clear suppression of tonically active neurones in substantia nigra pars reticulata. Released from potent GABAergic nigral inhibition, target neurones in the superior colliculus and ventromedial thalamus discharged vigourously. Output signals The manner by which the basal ganglia exert influence over target structures is by a fundamental process of disinhibition (Chevalier and Deniau 1990) (Figure 5). GABAergic neurones in the basal ganglia output nuclei have high tonic firing rates (40-80 Hz). This activity ensures that target regions of the thalamus and brainstem are maintained under a tight and relatively constant inhibitory control. Focused excitatory inputs from external structures to the striatum can impose a focused suppression, (mediated via "direct" GABAergic inhibitory connections), on sub-populations of output nuclei neurones. This focused reduction of inhibitory output activity effectively releases or disinhibits associated target regions in the thalamus (e.g. ventromedial nucleus) and brainstem (e.g. superior colliculus) from normal inhibitory control.

Function In humans, basal ganglia dysfunction has been associated with numerous debilitating conditions including Parkinson's disease, Huntington's disease, Tourette's syndrome,schizophrenia, attention-deficit disorder, obsessive-compulsive disorder, and many of the addictions. To understand and correctly interpret how a complicated system such as the basal ganglia can malfunction, it is useful to appreciate how the network works normally. What are the normal functions of basal ganglia circuitry? Two recurring themes in basal ganglia literature point to their involvement in action selection andreinforcement learning.

Figure 6: A conceptual model of action selection by the basal ganglia. Parallel processing functional systems that compete for behavioural expression are distributed throughout the brain, and are connected to the basal ganglia via a looped architecture (Alexander et al. 1986, McHaffie et al. 2005); examples of two such systems are illustrated. The selection hypothesis maintains that the input side of each loop carries phasic signals representing a bids for selection. Within the basal ganglia nuclei competing bids are evaluated and the tonic inhibitory output is withdrawn from selected channels and maintained on non-selected channels. A computer simulation of this architecture is able to generate coherent sequences of purposive behaviour when controlling action selection in an autonomous mobile robot (Prescott et al. 2006).

Action selection Despite numerous suggestions that the basal ganglia are involved in a wide range of functions including perception, learning,memory, attention, many aspects of motor function, even analgesia and seizure suppression, increasingly evidence points to an underlying role in basic selection processes (Mink 1996, Redgrave et al. 1999).

Selection is an old problem: The anatomical connections and neurotransmitters systems of the basal ganglia in vertebrate species are remarkably similar, suggesting that the evolution of these structures has been very conservative (Medina and Reiner 1995). Consequently, whatever computational problems the basal ganglia evolved to solve, they were likely to be as much problems for early vertebrates as they are for us today. A likely possibility is that multifunctional agents typically have to express different functional outputs through a shared motor resource - the final common motor path. A fundamental requirement is to determine which functional system should be allowed control of the motor output at any time. This selection problem is one shared by all vertebrates and has not changed materially over the course of evolution, despite great changes in the range, power and sophistication of systems competing for expression.

The basal ganglia can select: The macro-architecture of the basal ganglia appears to be configured for selection (Figure 6). The parallel loops originating from and returning to diverse cortically and sub-cortically based functional systems (Alexander et al. 1986, McHaffie et al. 2005) convey phasic excitatory signals (bids for selection) to the input nuclei. Depending on comparative magnitudes of "input saliences", channels returning to structures providing the most "salient" inputs would be selectively disinhibited. Returning disinhibitory signals may permit the sensory/cognitive inputs to the targeted functional system access to the shared motor resource. Maintained or increased levels of tonic inhibitory signals in nonselected channels would prevent the output of non-selected target structures accessing the common motor path. Independent of any biological considerations, a similar "centralselection" control architecture was devised to select the actions of an autonomous mobile robot (Snaith and Holland 1990). Subsequently, it has been confirmed that a biologically constrained model of basal ganglia architecture can do likewise (Prescott et al. 2006).

Figure 7: Proposed mechanisms for serial selection within the basal ganglia. 1. Strong synchronised inputs required to elevate themembrane potential of medium spiny neurones to an up-state whereaction potentials can be generated. 2. Local and longer range inhibitory connections between striatal neurones. 3. Focused signals from the striatum are superimposed on diffuse signalling from the subthalamic nucleus creating an inhibitory centre, excitatory surround at the level of the output nuclei. 4. Local recurrent inhibitory connections between elements of the output nuclei. All mechanisms contribute to the overall process of selective disinhibition.

Open and closed loops: A fundamental requirement for selection is that activity within the functionally segregated loops should interact. Consequently, at each major relay point within each of the basal ganglia loops (input nuclei, output nuclei, and the thalamus) signals flowing in the parallel channels can be subjected to influences originating outside the loop (Joel and Weiner 1994). With the selection hypothesis in mind, mechanisms within the internal circuitry can be identified that would promote "selection", in part by permitting different channels to influence each other (Figure 7):

Excitatory inputs to an individual spiny neurone must be sufficiently synchronised to depolarise the membrane of medium spiny neurones to an "up-state" where it can fire action potentials (Gerfen and Wilson 1996). This mechanism might represent an initial filter to exclude "weak" competitors.

Local inhibitory collaterals between striatal spiny neurones (Plenz 2003) and longer range inhibitory effects of interneurones (Tepper and Bolam 2004) should cause highly activated striatal elements to suppress activity in more weakly activated channels.

At the level of basal ganglia output nuclei, the imposition of focused inhibition from the striatum onto a more diffuse excitation from the subthalamic nucleus should cause an inhibited (selected) centre with an excitatory (non-selected) surround (Mink 1996).

Local inhibitory collaterals between output nuclei neurones (Mailly et al. 2003) should further "sharpen" the difference between inhibited and non-inhibited channels. Together these mechanisms can be viewed as a sequence of mechanisms for selection.

Canonical micro-architectures: The internal micro-architecture of each basal ganglia structure is retained across the representations of different functional territories. Insofar as function is an emergent property of connectivity, the presence of common architectures suggests that similar computational processes are applied to inputs from drastically different functional origins. It is noteworthy that goal directed behaviour can be conceived as a three tier hierarchy with selections required at each level (Redgrave et al. 1999):

selections of overall goal; selections of actions to achieve a selected goal; and selections of movements to achieve a selected action.

Thus, the same micro-circuitry shared by the different functional territories of the basal ganglia could, in principle, select between competing "goals", "actions" and "movements". It is therefore relevant that across the ventromedial-dorsolateral gradient proposed for the striatum (Voorn et al. 2004), inputs to ventromedial sectors come from structures in which competing behavioural goals may be represented (prefrontal cortex, amygdala, hippocampus), while the connections of dorsolateral sectors are from regions that guide movements (e.g. sensory and motor cortex). Consequently, it is not difficult, to map the conceptual framework of goal, action and movement selections onto the "spiral architecture" proposed by Suzanne Haber (Haber et al. 2000) for successive connections between the limbic, associative and sensorimotor territories of the basal ganglia. Reinforcement learning The basal ganglia have long been associated with the processes of reinforcement learning (Schultz 2006; see also Reward Signals). This should not be surprising since instrumental or operant conditioning (the class of learning most commonly linked to the basal ganglia) can be viewed as the biasing of future action selections by past action outcomes. One of the strongest lines of evidence supporting the involvement of the basal ganglia in reinforcement learning is

the electrophysiological data obtained from behaving monkeys. Typically, unexpected biologically significant events including sudden novel stimuli, intense sensory stimuli, primary rewards, and arbitrary stimuli classically conditioned by association with primary rewards evoke a stereotypic sensory response from DA neurones in many species (Schultz 1998). This response comprises a characteristic short latency (70-100 ms), short duration (<200 ms) burst of activity. However, it is the capacity of phasic DA responses to change when experimental conditions are altered that has provoked most interest.

d) Aetiology : The etiology of Parkinsons disease (PD) has long been thought to involve both genetic and environmental factors, but until recently there has been no direct evidence to support either one as a causative factor. However, in the past 8 years six different genes have been identified as causing familial PD. Together, they support the notion that common pathogenetic mechanisms exist across the etiologic spectrum of PD. Specifically, mutations in -synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2 cause PD, with a Mendelian pattern of inheritance. DJ1 and PINK1 are mitochondrial proteins and overexpression of -synuclein and parkin induce mitochondrial defects. These same proteins are involved in the response to oxidative stress and affect proteasomal function. In contrast, few environmental factors have been characterized. Nevertheless, those toxins that have been demonstrated to have the ability to cause nigrostriatal cell death appear to interact by interfering with mitochondrial function, inducing oxidative stress, and modifying proteasomal function. Therefore, common themes are beginning to emerge in the etiopathogenesis of PD. This bodes well for research focused on the development of treatments that will modify the course of PD.

e) C / F : There are 4 cardinal features of Parkinsons Disease that can be grouped under the acronym TRAP : Tremor at rest, Rigidity, Akinesia and Postural instability. In addition fixed posture and freezing have been included among classic features of Parkinsons Disease. Bradykinesia: Refers to slowness of movement and is the most characteristic clinical feature of Parkinsons Disease. It encompasses difficulty in planning, initiating and executing movements,with performing sequential and simultaneous tasks. Other manifestations include loss of

spontaneous movement and gesturing , drooling because of impaired swallowing ,hypophonic dysarthria, hypomimia (loss of facial expression) , decreased blinking, reduced arm swing while walking. Bradykinesia is usually tested by finger taps, rapid supination and pronation and foot tapping. A peculiar phenomenon observed is known as Kinesia paradoxica in which an immobile person may be able to perform quick movements during excitement and mental stress. Functional neuroimaging studies also suggest impairment of recruitment of cortical and subcortical systems that regulate kinematic parameters of movement. Anatomically the deficit appears to be localised in the putamen and globus pallidus resulting in reduction of muscle force produced at initiation of movement. Tremor: Rest tremor is the most common symptom. They are usually unilateral between 4 6 Hz and are prominent in distal part of extremities. Tremors are usually pill rolling type. Tremors can also involve lips, chin, jaw and legs but unlike essential tremors rarely involves head, neck or voice. Some patients have postural and kinetic tremor in addition. The postural tremor is often delayed after the patient assumes an outstretched position. About 69% patients have tremors at onset of disease, 75% develop it during the course of disease and in 11% tremors are absent. Clinicopathologic studies have demonstrated that patients with Parkinsons Disease and prominent tremors have degeneration of subgroup of midbrain(A8) where as this area is spared in patients without tremor. Rigidity: It is characterized by increased resistance usually accompanied by cog wheel phenomenon particularly when associated with underlying tremor. It may occur proximally and distally. Reinforcing maneuvers like voluntary movements of contralateral limbs (Froments manoeuvre) usually enhances rigidity. Postural Deformities Axial rigidity results in abnormal axial postures (anterocollis, scoliosis). Fixed posture usually occurs late in disease. Striatal limb deformities ( striatal hand and striatal toe) are also seen. Other skeletal abnormalities include extreme neck flexion, truncal flexion(camptocormia) and the Pisa syndrome in which there is tilting of the trunk particularly while sitting or standing. Postural Instability It is due to loss of postural reflexes. The pull test in which the patient is pulled backwards or forward by shoulders is used to assess the degree of retropulsion or propulsion respectively. Postural instability with freezing is the most common cause of falling. Gait Disturbance:

The Parkinsonian gait is typically referred to as a slow and shuffling gait with loss of arm swing, gait initiation problems, difficulty in turning around with a tendency for propulsion. Freezing also referred to as motor blocks is a form of akinesia and is one of the most disabling symptoms of Parkinsons Disease. It typically manifests as a sudden and transient(usually < 10 sec) inability to move. Five types of freezing have been described. 1. 2. 3. 4. 5. Start hesitation Turn hesitation Hesitation at tight quarters Destination hesitation Open space hesitation

Patients often develop tricks to overcome freezing attacks. This includes marching to command, stepping over objects, walking to music or beat and shifting body weight. Other motor abnormalities: Because of the breakdown of frontal lobe inhibiting mechanisms some patients demonstrate emergence of primitive reflexes. Glabellar tap reflex occurs in 80% of subjects. Bulbar dysfunction manifested as dysarthria, hypophonia, dysphagia and sialorrhoea can be observed. Speech disorder is characterized by slow and monotonous speech. A tip of the tongue phenomenon may be seen. Dysphagia and drooling of saliva may occur. Neuro- ophthalmologic abnormalities include reduced blink rate, upward gaze impairment, decreased convergence, slow saccades , antisaccades, blepharospasm and visual hallucinations. Oculogyric crisis and apraxia of eyelid opening can also occur. Respiratory disturbance in patients with Parkinsons Disease can be restrictive or obstructive. They may be associated with development of intercurrent pneumonia. Non-Motor Abnormalities : These include autonomic dysfunction, cognitive dysfunction, sensory and sleep abnormalities. Autonomic failure usually develops late in a typical Parkinsons Disease and presents as orthostatic hypotension, sphincteric dysfunction and erectile dysfunction. About 84% patients show cognitive decline and 48% of patients meet diagnostic criteria of dementia after 15 years of follow up. Other neuro-psychiatric problems like depression (58%), apathy( 54%) , anxiety ( 49% ) , hallucination (44%) were frequently reported. Excessive sleepiness and REM ( Rapid Eye Movement ) sleep behavioral disorders are seen in Parkinsons Disease. The REM sleep behavioral disorder is characterized by hypertonia in REM sleep with dream enactment.Olfactory dysfunction ( hyposmia) may be an early marker of Parkinsons Disease.

f) Investigation

g) Management : Medical : MEDICAL MANAGEMENT OF PARKINSON'S DISEASE

The management of Parkinson's disease has evolved rapidly over the last 10 years with the advent of new drugs, new classes of drug, and the resurgence of interest in surgery. Although there has been a move toward patients being cared for by neurologists or geriatricians with a special interest in the condition, along with a Parkinson's disease nurse specialist, for the foreseeable future most general neurologists will continue to treat patients with the condition. The present review uses an evidence based approach to provide an update on the current place of medical treatment for Parkinson's disease. Unfortunately, in light of the lack of evidence in many areas, it is not always possible to be prescriptive and many treatment decisions must be left to the judgement of the individual clinician and the desires of patients.

EARLY PARKINSON'S DISEASE

The major issues regarding the difficulty in the clinical diagnosis of Parkinson's disease have been outlined already in this supplement (see p i10). It will be assumed in this review that the patient has idiopathic Parkinson's disease with significant functional disability that requires treatment.

Neuroprotection
The definitions of terms in relation to neuroprotection are outlined in table 1 and fig 1. 1 The effects of this approach to treatment in Parkinson's disease can be measured in three ways:

Comparison of the mortality rate on the putative neuroprotective agent with that in a control population within the setting of a randomised controlled trial (RCT) Measuring the decline in 18F-fluorodopa uptake by dopaminergic neurones in the striatum using positron emission tomography (PET) to demonstrate reduced decline in the group treated with the neuroprotective agent During a total drug wash out period at the end of an RCT, rating scales (for example, unified Parkinson's disease rating scale (UPDRS), total or motor score) decline less in those treated with the neuroprotective agent.

Figure 1

Schematic representation of neuroprotective strategies in Parkinson's disease. An insult at the time point indicated by the upper arrow leads to an acceleration in the normal age related loss of nigrostriatal dopaminergic neurones. Treatment is commenced at the point indicated by the lower arrow. Note: (1) in view of debate about the rates of decline in dopaminergic neurones no baseline for the y axis has been given; (2) whether the decline in Parkinson's is exponential or linear, etc, is not known. Adapted from Parkinson's disease in practice, Royal Society of Medicine Press, 2001. All of these techniques suffer from significant problems. Demonstrating differences in mortality requires very large trials with national flagging to avoid missing the end point. PET is only available in a small number of centres so patients often need to travel distances to be assessed. The last method requires a complete wash out from all medication, including symptomatic treatments such as levodopa, that is rarely acceptable to patients. These and other issues have dogged the hunt for an effective neuroprotective agent in Parkinson's disease. Nevertheless, this must remain the holy grail of Parkinson's disease treatment as patients continue to die in excess of their peers. 2 Selegiline was introduced as an adjuvant treatment in later disease, but a retrospective study raised the possibility that it might reduce mortality and thus be neuroprotective. This was in keeping with its known ability to inhibit the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in experimental models of Parkinson's disease. This hypothesis was not confirmed by the DATATOP trial, and a UK Parkinson's Disease Research Group trial found increased mortality in those treated with selegiline, although a subsequent follow up analysis did not find a significant increase in mortality after correcting for baseline covariates. 3 If selegiline does have a neuroprotective effect, this is likely to be small and will require much larger trials to prove. Since the pathophysiological mechanism or mechanisms that cause Parkinson's disease are poorly understood, the rational development of neuroprotective agents has proved a difficult process. Neuroprotective strategies currently being accessed in clinical trials include the excitatory amino acid antagonist riluzole and the dopamine agonists pergolide and ropinirole. The excitatory amino acid glutamate, increased in the medial portion of the globus pallidus in Parkinson's disease, may be neurotoxic although no evidence of this is yet available in humans. Dopamine agonists reduce the accentuated compensatory turnover of dopamine which has been shown to be damaging in animal models.

Symptomatic treatment
Levodopa The dramatic clinical effect of levodopa in Parkinson's disease was first demonstrated in the early 1970s and remains the `gold standard treatment for this condition. The impressive results and the urgent needs of patients meant that RCTs were not performed. The next significant development was the addition to levodopa of the peripheral dopa decarboxylase inhibitors, benserazide and carbidopa, that reduced peripheral side effects such as nausea, vomiting, and postural hypotension and also increased the delivery of levodopa to the brain. Consequently, levodopa preparations became widely prescribed in the UK in the 1980s. In recent years there has been a move away from levodopa as the first line treatment, at least for young patients, in view of its involvement in the generation of the long term motor complications and the possibility that it may be neurotoxic. Motor complications comprise abnormal involuntary movements, including choreoathetoid dyskinesia, dystonia, and response fluctuations. The latter consist of a shortening response to each dose of medication (end-of-dose deterioration or wearing off effect) and unpredictable switching between the mobile on phase and relatively immobile off phase (on/off fluctuations). These affect 10% of patients with each year of levodopa treatment, so after five years of treatment 50% of patients will suffer from them. This rate of development of motor complications is worse in young onset patients (onset < 40 years of age) with 100% suffering from these complications after six years of treatment. Levodopa and dopamine are toxic to cultures of dopaminergic neurones. However, this is at supraphysiological doses and in the absence of glial cells that may inhibit neurotoxicity. There is no evidence that levodopa in vivo is neurotoxic, but this is currently the subject of a large ongoing North American trial (ELLDOPA trial). The convincing relation between levodopa and motor complications has led to the move away from immediate release levodopa preparations as monotherapy. However, the alternatives considered below must live up to the efficacy and safety profile of levodopa. Modified release levodopa The possibility that the pulsatile stimulation produced by immediate release levodopa preparations may be responsible for motor complications led to the development of modified or slow release levodopa/decarboxylase inhibitor combinations (Madopar CR and Sinemet CR). However, two studies comparing these with immediate release levodopa failed to show any difference in motor complication rates after five years of such treatment. Since

the modified release preparations are more expensive than traditional immediate release levodopa, there is little to recommend them at present in early disease. Anticholinergics Anticholinergics have been used in Parkinson's disease for more than 100 years, but it was the discovery of selective muscarinic antagonists with a more favourable side effect profile that led to their widespread use. Although many are available in the UK, benzhexol and orphenadrine are the most commonly used. A Cochrane systematic review of anticholinergic treatment in Parkinson's disease is underway. From the author's knowledge of the few trials in this area, anticholinergics are less effective than levodopa, apart from their beneficial effect on tremor, and have a worse adverse event profile, particularly in the elderly. Common central side effects are confusion, hallucinations, and transient cognitive impairment. Peripheral side effects include nausea, dry mouth, constipation, dizziness, blurred vision, precipitation of closed angle glaucoma, and urinary retention, especially in those with prostatic hypertrophy. Amantadine Initially investigated as an antiviral agent, amantadine was found by chance to be effective in Parkinson's disease. A Cochrane systematic review of the RCTs with amantadine is nearing completion but no comparative trials with levodopa have been performed. The clinical impression is that amantadine is less effective and the possibility that tolerance develops with long term treatment has been suggested by some. Like the anticholinergics, amantadine produces significant central side effects of confusion and hallucinations and peripheral reactions such as ankle oedema and livedo reticularis. Although the use of amantadine has declined in recent years, this may change if it is shown to be effective against dyskinesia in later disease. Several small trials have suggested that it may have such an effect, but much larger studies are required before it can be recommended for this use. Selegiline The possible neuroprotective properties of selegiline have been already considered. In terms of its symptomatic effects, in the DATATOP study selegiline delayed the need for levodopa by only nine months. Although no head-tohead comparison with levodopa has yet been performed, this suggests it has only a weak symptomatic effect compared with levodopa. It also has the disadvantage of causing significant sleep disturbance for some patients. Dopamine agonists The dopamine agonists were initially introduced as adjuvant therapy in late Parkinson's disease. However, the desire to delay the introduction of levodopa led to trials with agonists as monotherapy. The first trials of bromocriptine versus levodopa were reported in the mid 1980s and have recently been the subject of two Cochrane reviews. 4,5 In summary, these showed that bromocriptine when used alone delayed the onset of dyskinesia but not motor fluctuations. In contrast, bromocriptine used in combination with levodopa (as levodopa sparing treatment) showed no clear advantage over levodopa. These results with bromocriptine were echoed in the two small trials with lisuride or combined lisuride/levodopa versus levodopa alone; lisuride must be used alone to delay the onset of motor complications. Against this background, the manufacturers of the more recently introduced agonists each performed a single monotherapy trial with their agonist against levodopa (table 2). These showed significantly less motor complications in the agonist arms of each trial. However, in the published pramipexole6 and ropinirole7 studies those in the agonist arm had less improvement in motor impairments and/or disability (fig 2). This is surprising since these patients could have had the agonist dose titrated to the maximum tolerated and then open label levodopa could have been added. Presumably the patients were content for other reasons unrelated to motor impairments and disability. In terms of tolerability, hallucinations were significantly worse with ropinirole and somnolence with pramipexole. Withdrawals because of adverse events were greater with pergolide (18%) than levodopa (10%). Measures of health related quality of life may have given a more complete picture of patient's suffering in these studies. In the pramipexole study up to the two year evaluation there was no difference in quality of life between the two arms.

Table 2
Summary of modern dopamine agonist monotherapy trials

Figure 2
(A) UPDRS motor and (B) activities of daily living scores in the ropinirole versus levodopa study. Reproduced from Rascol and colleagues,7 with permission of the publisher. It appears from the trial evidence that dopamine agonist monotherapy produces less motor complications than levodopa, but at the expense of more adverse events and possibly reduced efficacy. This appears to be a class effect although only one trial comparing the effects of the agonists has been performed. In this trial of ropinirole versus bromocriptine monotherapy with rescue levodopa, there was no difference in the incidence of motor complications between the two agonists although activities of daily living scores were significantly more improved in the ropinirole group.

Remaining issues in the pharmacotherapy of early Parkinson's disease

In spite of the plethora of recent work addressing dopamine agonist monotherapy, many questions still remain. A change in practice to using agonist monotherapy for every new case of Parkinson's disease would double or treble the cost of treatment immediately. Is this worth it from the National Health Service's perspective in terms of cost effectiveness, and from the patient's perspective in terms of quality of life? Is agonist monotherapy neuroprotective and/or is levodopa toxic? It has been suggested that agonist monotherapy delays motor complications until levodopa is introduced, then complications accelerate until they are as severe as they would have been if an agonist had never been given. No data on this are available from the existing trials so this possibility remains. The recent agonist monotherapy trials included predominantly younger patients with Parkinson's disease: ropinirolemean age 63 years; pramipexolemean age 61 years; pergolidemean age 59 years. So the results of these trials should not be generalised to the elderly population in whom further data are required before recommendations can be made. Similar questions are outstanding regarding selegiline monotherapy in terms of its effects on quality of life, cost effectiveness, and neuroprotection. Many of these questions will be examined in the PD MED trial which is currently underway in the UK (fig 3). In the early disease 15003000 patients will be randomised to monotherapy with any levodopa preparation, any dopamine

agonist, or any monoamine oxidase (MAO) B inhibitor (in practice selegiline at present). They will be followed for a minimum of five years with monitoring of quality of life, health economics, mortality, and the incidence of motor complications.

Figure 3
Summary of the design of the PD MED trial (green arrows indicate optional randomisations). COMT, catechol-Omethyltransferase; MAOB, monoamine oxidase B.

LATER PARKINSON'S DISEASE

In the real world general practitioners continue to diagnose and treat early Parkinson's disease with levodopa, only referring patients once motor complications have arisen. At this stage there is a choice of adjuvant treatment aimed at reducing patient's off time, reducing levodopa dose, and improving motor impairments and disability with acceptable side effects such as increased dyskinesia.

Adjuvant treatment
Dopamine agonists The large number of RCTs examining agonist adjuvant treatment have been the subject of a number of Cochrane reviews by this author and others. The bromocriptine and lisuride versus placebo reviews failed to find sufficient evidence to reach any conclusions. The reviews of cabergoline, pergolide, pramipexole, and ropinirole versus placebo trials showed significant reductions in off time and levodopa dose with increased dyskinesia, but fewer withdrawals from the agonists. Other adverse events such as nausea, hallucinations, and somnolence were more frequent with the agonists. The recent concern about sleep attacks on pramipexole and ropinirole has raised awareness about the issue of somnolence, but this appears to be common with all dopaminergic treatment, even levodopa. No clear differences between the agonists were apparent from this meta-analysis, although this conclusion should be treated with caution since the agonists were not directly compared. From the perspective of clinical practice active comparitor trials are more valuable. Most of the modern agonists have been compared with bromocriptine in RCTs. Cochrane reviews of these have shown that cabergoline, pramipexole, and ropinirole produce 30 minutes more reduction in off time than bromocriptine, but otherwise there is no difference in the efficacy or safety of modern agonists compared with bromocriptine. Whether this additional reduction in off time with modern agonists is worth the additional cost cannot be calculated using health economics models as insufficient data are available in the UK on the cost of off time. This work has also allowed sample size calculations to be performed which show that trials of multiple agonists as adjuvant treatment would be prohibitively large (around 5000 patients) and expensive. Therefore decisions regarding which agonist to use cannot be based on efficacy or safety, but rather on issues such as dose frequency, ease of titration, and affordability. In later Parkinson's disease, when off periods become frequent and unpredictable in spite of optimal oral treatment, apomorphine injections or infusion can be used.8 Apomorphine is a potent dopamine agonist which is extensively metabolised in the liver, thus having poor oral bioavailability. Most of the data on apomorphine have come from small

non-randomised and uncontrolled studies, although a recent small placebo controlled study has confirmed the benefits of intermittent apomorphine injections. Apomorphine infusions cost around 10 000 per patient per year, although this may be offset by reductions in other costs such as residential care. Both intermittent injections and continuous infusions should be confined to specialist movement disorders clinics where clinicians and Parkinson's disease nurse specialists have experience with the techniques involved. Selegiline No systematic review of selegiline trials is available, but from the author's knowledge trials were small and of short duration with no measures of off time. Nevertheless they support selegiline reducing levodopa dose and improving motor impairments. While many clinicians believe selegiline is less effective than the dopamine agonists no evidence exists to support this view. In recent years a new formulation of selegiline has become available. The oral fast-melt Zydis preparation avoids first pass metabolism in the liver, and thus produces fewer amphetamine-like metabolites and possibly fewer side effects. The single randomised placebo controlled trial available showed similar reductions in off time as with agonists on the 2.5 mg/day dose and significant reductions in motor impairments and disability. COMT inhibitors Catechol-O-methyltransferase (COMT) inhibitors reduce the metabolism of levodopa to 3-O-methyldopa in the periphery thereby increasing the amount crossing the bloodbrain barrier. This produces a 3050% increase in levodopa half life and a 25100% increase in the levodopa concentration versus time curve, while leaving the maximum plasma concentration of levodopa unchanged. Tolcapone was the first COMT inhibitor licensed in the UK, but was withdrawn on account of several cases of fatal hepatic toxicity. Entacapone does not seem to suffer from this problem. Although clinical experience suggests that entacapone is not as effective as both agonists and tolcapone, the evidence from placebo controlled trials shows similar improvements in on time, off time, and levodopa dose as with dopamine agonists. Insufficient data are available on activities of daily living and motor impairments to reach any firm conclusion. Entacapone produced dopaminergic adverse events that were reduced by levodopa dose reduction, along with unexplained diarrhoea and discolouration of urine. A Cochrane review of COMT inhibitors is awaited. Modified release levodopa RCTs in patients with motor complications showed that Sinemet CR and Madopar CR produced moderate reduction in off time compared with immediate release preparations, but variable effects on dyskinesia with a tendency for these to increase. The doses of both modified release preparations had to be increased by 2060% because of reduced absorption and bioavailability. Adverse events were similar for immediate and modified release agents. Modified release levodopa also allowed a reduction in the number of daily doses compared with the standard formulation from an average of five to between three and four doses per day. In these trials, clinicians and patients preferred modified release to the immediate release preparation, although the results in general clinical practice have been less convincing.

Remaining issues in the pharmacotherapy of later Parkinson's disease

Although many believe dopamine agonists to be the most effective agents to use as adjuvant therapy, this conclusion is not evidence based. We require further data comparing agonists, COMT inhibitors, and selegiline in terms of quality of life and health economics. This is the subject of the second part of the PD MED trial (fig 3). Further information is also required on when to use apomorphine infusions, particularly in relation to surgical treatment. Answers should be generated in part from the PD SURG trial (see p 00).

PARAMEDICAL THERAPIES
Paramedical therapies have traditionally been used in later Parkinson's disease when significant functional disability has developed. Long waiting times for treatment for neurological patients, combined with a perceived lack of evidence of efficacy, has led to low referral rates in the UK despite the enthusiastic support of patients. RCTs of the main three paramedical therapies have recently been the subject of a series of Cochrane systematic reviews by the author and colleagues. There was insufficient evidence of the efficacy of physiotherapy, occupational therapy, or speech and language therapy for dysarthria or dysphagia in Parkinson's disease. It must be emphasised that lack of evidence does not mean lack of efficacy. Further trials are required to decide whether and when these treatments should be used. The UK Parkinson's Disease Society is in the process of developing large pragmatic trials of both physiotherapy and occupational therapy.

PARKINSON'S DISEASE NURSE SPECIALISTS

The development of specialist peripatetic nurses for Parkinson's disease has been led by the Parkinson's Disease Society in the UK. From small beginnings, around 100 are now funded from various sources including the NHS. The nurses have a number of roles but they primarily act as a key worker for the patient with Parkinson's disease, liaising with therapists, social services, the primary and secondary care teams, etc. They serve to educate the patient, relatives, and members of the medical and allied professions about the condition. Their ability to help the patient with complex changes in medication, including apomorphine infusions, within set limits can be invaluable. Parkinson's disease nurse specialists have been the subject of a recent large RCT which showed significant improvements in an open label patient global impression scale at no additional cost to the NHS. No advantages in quality of life or mortality were found, but the study was confounded by selegiline withdrawal.

SPECIALIST CLINICS
Although over the last 10 years there has been a move towards specialist movement disorders or Parkinson's disease clinics, there is no evidence that they provide better care than standard neurology or geriatrics clinics. However, a recent study from Wales showed that the diagnostic error rate in parkinsonian syndromes was over 50% in general practice. Brain bank studies show an error rate of around 25% in neurologist's hands, but this reduced to only 8% in the DATATOP study in which committed clinicians with a particular interest in Parkinson's disease took part. This circumstantial evidence suggests that, at least from the diagnostic point of view, specialist clinics may be worthwhile.

GUIDELINES
Several sets of guidelines for the management of Parkinson's disease have been produced in the UK 9 and the USA,10 but these failed to use a rigorous procedure to sift the evidence before a panel of experts synthesised such data and made their recommendations. For the moment these should be treated with some caution. The treatment algorithm from a UK guidelines panel is shown in fig 4.

Figure 4
Treatment algorithm for Parkinson's disease. CR, controlled release; GP, general practitioner.

Surgical :

Surgical Treatment of Parkinson's Disease

Parkinson's disease (PD) is a neurological disorder that affects movement. Brain cells that produce dopamine, a chemical that directly affects coordination and movement, die when someone has PD. The lack of dopamine slows down coordination, causes involuntary movements and may also affect a person's cognitive function. Medications can be used to calm the nervous system and to help control spontaneous movement. When medication does not help Parkinson's disease symptoms enough, surgical treatment may be considered, according to the Parkinson's Disease Foundation (PDF).

Pallidotomy
o

In 1952, the first pallidotomy was performed and brought relieve to the Parkinson's disease patients who were severely affected by tremors and rigid limbs and muscles (see Resources). Pallidotomy is the surgical procedure that kills some of the overactive cells that are part of the globus pallidus area on one of the brain. The patient is asked to respond to questions or other stimuli to see if the procedure is successful. Surgeons achieve this result by creating a small hole in the PD patient's skull while the patient is awake, yet adequately sedated so that no pain is felt. Pallidotomy can be performed more than once if necessary. In rare cases, complications of this type of brain surgery occur and can affect a person's language skills.

Thalamotomy
o

Parkinson's disease patients who find no drug-induced relief of severe tremors in their arms and hands may discuss the option of having a thalamotomy with their doctors. The U.S. Food and Drug Administration (FDA) refers to the thalamus portion of the brain as the "communication center." By destroying some of the cells in the thalamus, a thalamotomy can help the small percentage of people with PD who are robbed of their fine motor skills due to the progressive disease. The FDA estimates that an impressive 90 percent of patients who have undergone a thalamotomy find an extreme reduction of their tremors (see Resources).

Deep Brain Stimulation

o

Deep brain stimulation, or DBS, is the newest type of surgical treatment for Parkinson's disease and is widely accepted as a way to stop the progression of the disease. The mechanics of DBS are similar to that of a pacemaker that shocks the heart back into a normal rhythm. A set of electrodes is implanted into the patient near his collarbone. The electrodes send impulses to the nerves that are in charge of movement and motor skills, in an effort to induce them to respond properly. DBS can help calm symptoms of PD, yet it is not without its risks. Due to the nature of the surgery, electrocution is a rare, yet very real risk, as is the chance of having a stroke. DBS is generally reserved for those who are extremely disabled, rather than moderately affected with Parkinson's disease and who do not find relief from drugs.

Candidacy for Surgery

o

Considering surgical treatment for Parkinson's disease is a huge decision, and as such, not one to be taken lightly. The PDF suggests that PD patients who are experiencing cognitive symptoms such

as dementia may not be ideal candidates for surgery, especially DBS, because of the risks that surgery carries. Being in otherwise good physical health is another requirement for PD surgery. Age is not necessarily a disqualifying factor if the person is in good health, yet the typical person who has chosen surgery has had PD for an average of 10 years. Parkinson's disease patients, their families and team of doctors should make the decision about whether to have surgery together.

Lasting Results
o

Positive results for PD surgeries can only last so long until the impaired portion of the nervous system takes over and begins its decline once again. Unfortunately, some patients who have had a pallidotomy will need to have the procedure repeated, either on the same side or other side of the brain, within a few years. Deep brain stimulation has a better record, with positive results lasting for at least 5 years in most people.

Physiotherapy:- Frenkels Exercise

Parkinson's disease and physical activity

People with disabilities are less physically active than those without disabilities. In PD, individuals at an early and moderate stage of the disease have greater reduction in physical activity level than asymptomatic individuals of the same age (Goulart et al. 2004). Furthermore, inactivity is considered an important factor in accelerating the degenerative process of PD (Tillerson et al. 2002). Otherwise, there is consensus in the literature that regular exercise practice improves physical and functional performance in different populations (Nelson et al. 2007, Dalgas et al. 2009). The practice of regular physical activity seems to be preventive for individuals both pre- and post diagnosis of Parkinson's disease. Some epidemiological studies have suggested there is an inverse relation between physical activity and risk of PD, i.e., moderate and high levels of physical activity are associated with lower risk in developing the disease (Chen et al.2005, Sasco et al. 1992 ). In addition, the study by Tsai et al. suggested that regular physical activity can delay the onset of symptoms in patients with PD (Tsai et al. 2002). A growing number of studies suggest that the exercises treatment approach brings greater benefits in functional performance in individuals with PD than isolated medication use and surgical procedures (Ellis et al. 2005, Ridgel et al. 2009). The participation of individuals withPD in physical exercise programs has shown to be effective in reducing co-morbidities, disuse and limitations caused by this disease. Different types of exercises were proposed by randomized controlled trials in order to minimize the negative effects of the PD on motor and functional performance. These studies have focused on different physical therapy approaches, such as specific exercises to improve mobility (Schenkman et al. 1998), muscular strength (Dibble et al. 2006, Dibble et al. 2009), balance (Hirsch et al. 2003), aerobic conditioning (Herman et al. 2007) and gait (Nieuwboer et al., 2007).

The results of these studies opened a way for the development of an evidence-based practice in the treatment of PD. In addition they can guide the clinical management of professionals working with individuals who present with this disease.

Exercises to improve mobility

Decreased flexibility decrease in the body axis of individuals with PD may interfere with their balance and impair performance of activities that require trunk mobility. A study by Vaugoyeau et al. demonstrated that an increased tonus of the body axis in individuals withPD results in "en bloc" axial movement, and also disturbs the execution of important activities such as movement in bed and turning while walking. Schenkman et al. developed a program which emphasized exercises for axial mobility associated with muscle relaxation and diaphragmatic breathing to increase range of motion of the neck and trunk. The results showed that 10 weeks of exercise improved in axial mobility and postural control of individuals with PD (Schenkman et al. 1998). Recently, Schenkman suggested that postural control and functional capacity specific training should incorporate axial mobility exercises to maximize gains in physical and functional performance as a whole (Schenkman 2010). (see Rodriguez JW et al., 2006).

Exercises to improve muscle strength

Recent studies have shown that muscular strength is reduced in Parkinson's patients when compared to individuals without the disease (Inkster et al. 2003, Nallegowda et al. 2004, Allen et al. 2009). The cause of decreased muscular strength remains unclear. However, it is believed that central mechanisms may be responsible through the reduction of facilitative stimulus for motoneurons (Glendinning 1997). Despites the causes, individuals with PD often complain of weakness in their lower limbs. Researchers have observed the presence of some selectivity in the distribution of muscle weakness (Corcos et al. 1996, Bridgewater & Sharpe 1998). Clinically, there is an inability of proximal and axial muscles to generate adequate power, especially the extensors of the trunk and hip. It is possible that the selective alteration in muscular strength contributes to a flexion posture, gradually observed in patients. The ability to perform various functional activities such as sitting to standing and walking can be compromised due to muscle weakness in the lower limbs of individuals withPD (Inkster et al. 2003, Nallegowda et al. 2004, Schilling et al. 2009). Strength training programs were effective in increasing muscular strength, and in some cases, the mobility of individuals with PD (Scandalis et al. 2003, Hass et al. 2007). These programs were implemented in a relatively short period of time with a training frequency of 2-3 times per week, one set of exercise per muscle group, and involved only concentric contraction. More recent studies suggested muscular strength and functional gains are greater when high-intensity protocols are used involving primarily eccentric contraction (Dibble et al. 2006, Dibble et al. 2009). The principle of this type of exercise is that high levels of force are generated during muscle stretching with minimal oxygen consumption in relation to the amount of work produced (Lastayo et al. 1999). Some studies have found that high intensity strength training was better for motor and functional performance in individuals with PD than training based on flexibility exercises, balance and concentric strength training of limbs (Dibble et al. 2006, Dibble et

al. 2009). It is possible that these results are associated with a greater muscle hypertrophy observed in the high intensity protocol group. According to Dibble et al., the observed increase in muscle volume may be important for improving muscular strength and mobility of PD patients. Moreover, high-intensity training can minimize loss in bone integrity, preserve eccentric muscular strength and promote metabolic and structural plasticity in the musculoskeletal system (Pang & Mak 2009, Falvo et al. 2007). Thus, it is possible that high-intensity exercises are most desirable to minimize the progressive dysfunction of PD. However, since individuals with PD have a lower physical fitness and are often unmotivated to practice physical activity, it is necessary to raise awareness about the use of high-intensity exercise in their treatment, since such exercise will require more physical effort which could lead to individuals' fatigue.

Exercises to improve balance

Despite medical treatment, individuals with PD fall frequently with devastating consequences (Canning et al. 2009). Approximately 66% of individuals with PD will suffer falls and 46% will experience recurrent falls (Wood et al. 2002). Factors such as gait freezing, muscular weakness and balance disorders were found as causes of falls in individuals with PD (Boonstra et al. 2008, Toole et al. 2000, Olanow & Koller 1998). Accordingly, different authors have used external cues for gait training, balance exercises, and strength training programs (Hirsch et al. 2003, Dibble et al. 2006, Nieuwboer et al. 2007) finding improvement in each of these factors. Hirsch et al. showed greater gains in muscular strength and balance when individuals withPD underwent a combined protocol of strength and balance training compared to the balance exercises group. After the intervention, the combined group had an increase of 52% in muscular strength, better performance in balance and permanence of gains after four weeks. It is possible that the intensity of strengthening exercises with 80% of the maximum resistance elicited permanent non-hypertrophic muscle adaptations favoring maintenance of the effect after one month of intervention. Recently, an exercise program was developed with the aim of delaying the progressive loss of mobility associated with balance and gait disorders in individuals with PD (King & Horak 2009). In this program, movements used in techniques such as "Tai Chi" and Pilates can be combined in order to facilitate sensory integration in postural control. Thus, somatosensory information can be encouraged by large and coordinated movements in order to move the center of mass with speed, safety and balance (King & Horak 2009). Some recent studies have investigated the effects of "Tai Chi" in motor and functional performance of individuals with PD (2008 Hackney & Earhart, MS et al. 2008). Hackney & Earhart showed that individuals with PD practicing "Tai Chi" for 13 weeks achieved gains in balance and functional performance when compared to the control group without intervention. The authors suggest that "Tai Chi" can be a safe and beneficial exercise in the treatment of moderately to severely affected PD patients (Hackney & Earhart 2008). Nevertheless, a recent literature review concluded that the evidence is not sufficient to support "Tai Chi" as an effective treatment for PD patients yet (MS et al. 2008). Therefore, further studies are needed to assess the possible effects of "Tai Chi" in improving balance and reducing the occurrence of falls in individuals with PD.

The physiological mechanisms involving gain of muscular strength and balance is not well known. The results of the studies mentioned strongly suggest that the postural control in PDmust be worked through exercises that involve both somatosensory and musculoskeletal systems so individuals will be able to respond to sudden center of mass perturbations inherent in daily activities. A recent study investigated the circumstances of the occurrence of falls in 124 patients withPD (Ashburn et al. 2008) and observed that most falls occurred at home. The main causes were tripping on obstacles and falling while standing, i.e., one in three falls occurred in the standing posture (Ashburn et al. 2008). Therefore, physiotherapists should address specific training in standing position, such as activities involving clothing and hygiene. Therapists should also carry out an environmental assessment in order to remove possible obstacles and suggest holders such as handrails and / or walking aids. Importantly, the use of mechanical supports for walking should be investigated and its prescription should be made with caution. Based on the slowness in adapting to changes in support surfaces and difficulties in performing simultaneous activities (Morris 2000), such as walking and moving the stick at the same time, patients with PD may fall during walking using a mechanical support as it becomes a potential destabilizing agent.

Exercises to improve physical conditioning

Individuals with PD show loss in muscle and cardiorespiratory function. These individuals have similar levels of maximal aerobic capacity when compared to asymptomatic individuals, but the maximum peak occurs at lower intensities of exercise suggesting low metabolic efficiency (Protas et al. 1996). This result is consistent with recent studies that have shown a lower cardiovascular response in individuals with PD (Barbick et al. 2007, Oka et al. 2006). According to Protas et al., these individuals spend about 20% more energy than healthy individuals during exercise stress testing, which may indicate reduced movement efficiency due to the higher energy cost required for the test. Aerobic exercise programs on a treadmill and walking training showed improvement in gait and quality of life of individuals with PD (Herman et al. 2007, Rodrigues-de-Paula et al.2006). The study by Rodrigues-de-Paula et al. demonstrated a significant improvement in quality of life after a strength training program and aerobic exercises using walking and stepping activities with heart rate monitor. The advantage of this training is that it can be applied clinically, since it does not require complex or expensive equipment. Recently, Muhlack et al. suggested aerobic exercise can improve the effectiveness of levodopa, and therefore patients' motor response. As suggested in some studies using animal models, it is also possible that regular and intense aerobic exercises produce a neuroprotective effect and contribute to the restoration of neuronal pathways impaired by the PD (Fisher et al. 2004, Pothakos et al. 2009). Despite some promising results, few studies have investigated the effect of aerobic fitness in physical function of individuals with PD. Thus, this subject needs more through exploration.

Exercises to improve gait

Gait impairment is an important clinical manifestation of PD and is considered as one of the most disabling aspect of this disease (Herman et al. 2009). Gait related mobility problems have a negative impact on quality of life and well being of individuals with PD (de Boer et al.1996, Martinez-Martin 1998). Despite advances in medical therapy and surgical techniques, gait dysfunctions are observed throughout the disease with limited improvement of symptoms (Bloem et al. 2004). From a physical therapy standpoint, several studies have emphasized the contribution of specific exercises and intervention strategies to improve gait in individuals with PD. Treadmill training, use of external cues and specific task training have been investigated and different parameters of gait and quality of life of these individuals (Nieuwboer et al. 2007, Miyai et al.2000, Miyai et al. 2002). According to Herman et al., treadmill training can promote a more stable and dynamic gait pattern in individuals with PD. Furthermore, some studies suggested that treadmill training is more effective in improving gait than other traditional approaches (Miyai et al. 2000, Miyai et al. 2002). It is possible that this intervention is beneficial because the subject is induced to maintain a steady rate with regular and uniform speed through the generation of rhythmic gait cycles due to periodic somatosensory and vestibular receptor stimulation (Frenkel-Toledo et al. 2005a, b, Toole et al. 2005). Thus, stimuli are transferred to neural circuits modulating gait in different central nervous system levels with rhythmic steps. Therefore, training on a treadmill can be seen as a kind of external cue to trigger the motor activity to be performed (FrenkelToledo et al. 2005 b). A recent review suggested that training on a treadmill can be performed in combination with physiotherapy at a frequency of three times per week, for about 20-30 minutes (Herman et al. 2009). For these authors, long-term treadmill training without weight-bearing is a safe and economical method to increase gait speed, restore gait rhythm and improve the quality of life of individuals with PD. Moreover, these effects may last for several weeks after the end of training (Miyai et al. 2002, Hermanet al. 2007). External visual and auditory rhythmic cues are important features in the treatment of PD, although not widely used in clinical practice. Studies have shown improvement in electromyographic and spatio-temporal parameters of gait in Parkinson's patients undergoing gait training with auditory, visual and tactile cues, (Thaut et al. 1996, Muller et al.1997, Marchese et al. 2000, Lewis et al. 2000, Nieuwboer et al. 2001). Cues are defined as environmental stimuli or the one generated by the patient, consciously or not to facilitate automatic and repetitive movements (Kwakkel et al. 2007). Although the way which cues improve movement is not clear yet, recent neurophysiologic studies have suggested theoretical mechanisms for how external cues affect movement performance (Rowe et al.2002). Thus, it is believed that individuals with PD have a lower activity in certain brain areas which are responsible for the internal markup needed to implement automatic and sequential movements, common for most of our motor activities (Rowe et al. 2002). It is also possible that individuals with PD can use alternative circuits such as the pre-motor parietal-thalamic pathways, which are usually activated by external stimuli in individuals without neurological disorders (Kwakkel et al. 2007).

Recently, Nieuwboer et al. demonstrated that three weeks of external cue training at home improved walking speed, step length and freezing severity of individuals presenting these frequent and disabling symptoms. Each individual chose their preferable cue modality (auditory, visual or somatosensory) and was trained in a variety of situations and daily activities. The authors suggested that further studies should be performed to develop duration and intensity criteria as well as the most appropriate training period so the benefits obtained through the use of cues in individuals with PD would be extended for as long as possible. Task specific training proved to be more effective than traditional exercises to improve functional performance in individuals with neurological disorders such as stroke survivors (Sullivan et al. 2007, Wolf et al. 2008). For example: Task specific training during treadmill walking with body-weight support is more effective in improving walking speed and maintaining these gains at six months than resisted leg cycling alone (Sullivan et al. 2007). This type of training has proven to be beneficial in gait and balance restoration in individuals with PD (Morris et al. 1996, Jobges et al. 2004, Lehman et al. 2005). Lehman et al. showed improvement in gait velocity and step length in individuals with PD after 10 days of walking and specific orientations for a longer step length. The literature indicates that learning is more effective when the task is carried out repetitively, and generalized to different contexts (Carr & Shepherd 1998). Even though, studies are needed to explain the mechanisms behind this type of motor training at improving different mobility aspects in individuals with neurological disorders such as Parkinson's.

Exercises on brain's health of individuals with PD

Recent studies in neuroscience have shown the effect of exercise on the brain's function through animal models with neurological disorders (Petzinger et al. 2007, Pothakos et al.2009). These studies have emphasized the role of exercise on neuroplasticity (the brain's ability to form new synaptic connections) and on brain self-repairing. These findings suggest that intensive exercise programs can improve brain performance in individuals with PD. Changes in brain function changes through physical activity can lead to behavioral alterations as a result of the plasticity mechanisms and protection of brain function (Tillersonet al. 2002, Fisher et al. 2004). Some studies have shown that exercise can restore motor function through a variety of molecular repair mechanisms in the basal ganglia circuit affected by PD (Fisher et al. 2004, Petzinger et al. 2007). Fisher et al. initiated an intensive and progressive protocol of training on a treadmill in rats with PD for 30 days at a frequency of 2 times a day. The results showed significant improvement in motor performance of animals (running duration and speed). Moreover, changes were observed in neurotransmitter interaction (i.e. glutamate-dopamine) and were considered as a possible mechanism responsible for the neuroprotective effect of exercise. Petzinger et al. using the same protocol showed similar motor gains in treadmill performance and an increase in dopamine release within the motor basal ganglia area. Tillerson et al. 2002 suggested that the molecular mechanism responsible for cerebral protection may require continued use of the exercise. In addition, the results of other studies highlighted the importance of exercise intensity and suggested that PD patients without specific contraindications should be encouraged to practice physical activities in a higher intensity than that self-selected by the patient (Hirsch & Farley 2009).

The emerging knowledge about the effects of physical exercise on brain function is accompanied by more information about the effects of physical inactivity in PD. Nowadays, it is possible to have a better understanding on the consequences of lack of exercise not only in the musculoskeletal system, but also in the brain's ability to respond negatively to a lack of stimulus. Studies showed that periods of inactivity or stress in PD can revert protection and behavior benefits gained by doing regular physical activities leading to deterioration of brain's function and disease progression (Tillerson et al. 2002, Howells et al. 2005). The results highlighted above demonstrate the ability of the PD brain to restructure under some circumstances. However, it is important to take caution in generalizing these findings to the whole population of individuals with PD. The results should be the basis for further research conducted in humans allowing a better understanding of the effect of exercise on brain's function in individuals with PD.

Conclusion
Multiple studies point to the benefits of exercise in improving muscular strength, flexibility and balance with subsequent functional improvement in individuals with PD. However, the information in the literature suggests that physical activities require some specific characteristics for this population. Exercises focusing on strength training, balance, aerobic conditioning as well as the use of external cues during gait can result in overall improvement in motor performance and quality of life related to PD patients' health. Moreover, according to studies using animals with PD, it is possible that intensive exercise contributes to brain repair and hence reversing the progressive functional damage of this disease in humans. Therefore, efforts should be implemented in the clinical and investigative research to gather more information related to more effective types of exercises, its frequency and program duration.

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