Parkinson’s disease is an advancing, unknown cause, neurodegenerative disorder. Due to depletion of dopamine-producing neurons in the basal ganglia of the brain, patients with Parkinson’s disease experience deterioration in balance and postural control, and progressive reduction in the speed and amplitude of movements (Morris et al, 2001). Movement disorders are the hallmark of Parkinson’s disease and can severely compromise an individual’s ability to perform well-learned motor skills such as walking, writing, turning around and transferring in and out of bed (Morris et al, 2001).
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The number of older individuals affected by PD makes it the second most common neurodegenerative illness after Alzheimer’s (Kristjanson et al, 2005). In Canada and the US, the prevalence is estimated to be 369 per 100,000 individuals with the number of individuals affected increasing with age (Bunting-Perry, 2006) and it is estimated that 10,000 new cases are diagnosed each year in the UK. It is a complex disorder caused by genetic, a variety of biological and environmental causes. One of the significant characteristics of PD is the dementia, which is thought to be due to the failure of dopaminergic neurons.
In several cases the illness can be inherited as an autosomal dominant or recessive attribute but in the majority of cases it is acquire. The biological etiology of the disease is indefinite. The discovery of variation in the parkin gene in the autosomal dominant case and alpha-synuclein gene in autosomal recessive cases has unlocked a new possibility for studies to recognize the essential biochemical process of pathogenesis.
The etiology of Parkinson’s disease (PD) has long been belief to affect both genetic and environmental factors, but until recently there has been no direct proof to sustain either one as a contributory factor. The pathological characteristic of PD is loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) with succeeding loss of dopamine (DA) in the nigrostriatal system and the occurrence of cytoplasmic addition, termed Lewy bodies.
In adding up, there is noticeable loss of non-DAergic neurons, mainly in the caudal brainstem, and these may turn out to be involved even before the DAergic neurons (Braak and others 2006). There is increasing agreement among parkinsonologists that PD is most likely not a homogenous disease but a syndrome of diverse disorders, caused by genetic, environmental, and other factors (Moore and others 2005; Klein and Schlossmacher 2007; Schapira 2008). Although the means of neurodegeneration in PD is not apparent, multifactorial causes corresponding different, although perhaps joining, pathways have been projected.
The pathogenesis of PD has been assumed to effect from a complex relations between environmental and genetic factors leading to mitochondrial dysfunction, oxidative stress, inflammation, and excitotoxicity, eventually leading to nigral DAergic neuron degeneration (Moore and others 2005; Klein and Schlossmacher 2007; Schapira 2008). Damaged degeneration of misfolded and aggregate proteins is being progressively accepted as playing a significant part in the pathogenesis of PD. Besides the widely studied ubiquitin-proteasome system, an autophagy-lysosome pathway has been getting growing consideration as an significant mechanism concerned in the repair and removal of misfolded proteins (Hegde and Upadhya 2007; McNaught and others 2007; Pan and others 2008).
Defects or dysfunction of certain genes, such as α-synuclein gene (PARK1), parkin gene (PARK2), ubiquitin carboxyl-terminal hydrolases (UCHL-1) gene (PARK5), PINK1 (PARK6), DJ-1 (PARK7), LRRK2 (PARK8), and Nurr1, have been accounted to be connected with familial PD (Moore and others 2005; Klein and Schlossmacher 2007). It is thought that mutations in the α-synuclein gene, parkin gene, and UCHL-1 may result in the breakdown of degradation of misfolded proteins, leading to neurodegeneration (Moore and others 2005; Klein and Schlossmacher 2007).
The causes and the development of disease in PD are unknown. The processes that are responsible for cell death are not known either, but a number of factors such as mitochondrial dysfunction, oxidative stress, excitotoxins, and neurotrophic factors are implicated as contributory agents (Lang, 1998). Restraint of a process of complex I activity (30%–40%) in the substantia nigra of irregular PD patients and changes of mitochondrial complex I are in conformity with the premise that there is mitochondrial abnormality (Kosel et al, 1998).
This notion is supported by the progress of severe Parkinsonism in subjects exposed to the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine), which take actions via inhibition of complex I (McNaught, 1995). Likewise, deficiency in mitochondrial respiration has been shown to cause the series of PD (Cohen, 1997). In addition, activation of glutamatergic N-methyl-D-aspartate (NMDA) receptor, as well as the re generative and protective effects of glial-derived and brain-derived neurotrophic factors on dopaminergic neurons, suggests that these factors play a key role in neuronal survival (Beck, 1995). Consequently, cell death in PD involves a succession of events.
Oxidative stress and the accumulation of cell-damaging free radicals have also been implicated in cell death in PD. An increase in levels of lipid peroxidation, iron, and
8-hydroxy deoxyguanosine and a reduced glutathione level in substantia nigra suggest a role for free radicals and oxidative stress in PD (Jenner, 1994). However, levels of many antioxidants such as ascorbic acid, glutathione peroxidase, alpha-tocopherol, catalase, and Cu/Zn- and manganese-dependent superoxide dismutases are either normal or increased in substantia nigra (Marttila, 1988). It is possible that a change in mitochondrial function together with increased production of free radicals may lead to energy loss, which may contribute to cell death (Schapira, 1994). On the other hand, there is no proof to confirm thoroughly that free radicals are the principal cause in nigral cell death in PD.
The discerning loss of neurons entails a more detailed clarification. Oxidative stress and free radicals may be general characteristics, rather than being definite for a number of neurodegenerative diseases. Many studies suggest that exposure to various toxins (e.g., pesticides) may cause symptomatic forms of Parkinsonism (Menegon, 1998).
Although exposure to herbicides, pesticides, and well water may have a causative role in some individuals, such exposures are very limited in the general population and not all people exposed to these chemicals develop PD (Semchuck, 1992). However, we can not rule out the possibility that genetic susceptibility mediated by xenobiotic-metabolizing enzymes such as cytochrome P450, N-acetyltransferase-2, and glutathione transferase may be involved in the pathogenesis of PD (McCann, 1997).
Clinical Symptoms of Parkinson Disease
Parkinson’s disease (PD) is a progressive neurological disorder distinguished by a large number of motor and non-motor characteristics that can influence on function to a changeable degree. Neuropsychiatric evidences take place in most of patients with Parkinson’s disease, and are related with impaired quality of life for patients and relatives, further decline of purpose and increased use of health resources. Medical and surgical treatment can bring on or get worse of such indications.
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There are four key features of PD that can be clustered under the acronym TRAP: Tremor at rest, Rigidity, Akinesia (or bradykinesia) and Postural instability. Because of the varied profiles and lifestyles of those affected by PD, motor and non-motor impairments should be assessed in the situation of each patient’s needs and goals (Jankovic, 2007).
Bradykinesia refers to sluggishness of movement and is the mainly characteristic clinical feature of PD, though it may also be seen in other disorders, including depression. Bradykinesia is a trademark of basal ganglia disorders, and it includes difficulties with planning, initiating and executing movement and with performing sequential and simultaneous tasks (Berardelli, 2001). The early expression is often slowness in performing activities of daily living and slow movement and reaction times (Giovannoni, 1999). Additional signs of bradykinesia include loss of natural movements and gesturing, drooling because of impaired swallowing, monotonic and hypophonic dysarthria, loss of facial expression (hypomimia) and decreased blinking, and reduced arm swing while walking (Bagheri, 1999).
Rest tremor is the most frequent and easily known symptom of PD. typically, rest tremor fades away with action and during sleep. Some patients also report an “internal” shaking that is not related with a noticeable tremor (Shulman, 1996). In addition to rest tremor, many patients with PD also have postural tremor that is more well-known and disabling than rest tremor and may be the primary expression of the disease (Jankovic, 1999). Parkinson’s related postural tremor (“re-emergent tremor”) is distinguished from essential tremor in that the manifestation of tremor is often delayed after the patient assumes an outstretched horizontal position (Jankovic, 1999).
The incidence of rest tremor is changeable among patients and during the path of the disease. In one study, Hughes and colleagues reported that 69% of patients with PD had rest tremor at disease onset and that 75% had tremor during the course of their disease.. Others have reported that a small percentage of patients (11%) never have tremor although a future study in patients with autopsy proven disease found that 100% of patients had tremor at some point (Rajput, 1991).
Rigidity is characterized by increased resistance, usually go along with the “cogwheel” incident, mainly when linked with an underlying tremor, present throughout the range of passive movement of a limb (flexion, extension or rotation about a joint)39.
Rigidity may be associated with pain, and painful shoulder is one of the most common early manifestations of PD although it is usually misdiagnosed as arthritis, bursitis or rotator cuff injury (Stamey, 2007). A potential study of 6038 persons (mean age 68.5 years) with no confirmation of dementia or parkinsonism at baseline found that the presence of stiffness, tremor and imbalance were each associated with increased risk for PD (hazard ratios 2.11, 2.09 and 3.47, respectively) (de Lau, 2006).
Postural instability (along with freezing of gait) is the most common cause of falls and contributes considerably to the risk of hip fractures (Williams, 2006). The long latency to the onset of falls distinguished PD from other neurodegenerative disorders, such as progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) (Wenning, 1999). In one study, the standard time from onset of indications to the first fall was 108 months in patients with PD in contrast with 16.8 and 42 months, correspondingly, in patients with PSP and MSA (Williams, 2006).
Numerous other factors also influence the incidence of postural instability in patients with PD. These include other parkinsonian symptoms, orthostatic hypotension, age related sensory alteration and the ability to put together visual, vestibular and proprioceptive sensory input (kinesthesia) (Bronte-Stewart, 2002). The fear of falling can further impair balance control in patients with PD (Adkin, 2003). In one study, 38% of those assessed experienced falls, and 13% fell more than once a week (Koller, 1989). As predicted, the regularity of falls interrelated with the severity of disease (Koller, 1989).
Treatment (dopaminergic therapy, pallidotomy, deep brain stimulation) can advance some axial signs (Roberts-Warrior, 2000) but typically does not strongly improve postural unsteadiness, measured by platform tilt and visual tilt (Maurer, 2003). Targeting other nuclei for deep brain stimulation in addition to the subthalamic nucleus and globus pallidus, such as the zona incerta and pedunculopontine nucleus, is being discovered as a possible surgical management of gait difficulties and postural constancy (Stefani, 2007).
Diagnosis of PD remains scientific with no dependable test obtainable. Diagnosis can be complicated and depend on the identification of the fundamental characteristics of bradykinesia, stiffness and shake. This can be complex in the elderly by the occurrence of co-incidence such as dementia or cerebrovascular disease. The diagnosis of PD is supported on a careful taking of medical record and a methodical bodily examination. At present, there are no laboratory tests or imaging studies that verify the diagnosis (Nutt and Wooten, 2005).
The accurate diagnosis of PD is vital for prognostic as well as therapeutic reasons. Research of the analytical precision for the disease and other types of Parkinsonism in community-based trials of patients undergoing anti-parkinsonian medication recognized a diagnosis of Parkinsonism in only 74 % of patients and clinically probable PD in 53 % of patients (Tolosa, et al., 2006). Clinicopathological studies based on brain bank substance from the United Kingdom and Canada have revealed that clinicians identify the disease inaccurately in about 25 % of patients; such studies explained that the most common grounds for investigative errors were presence of indispensable tremor, vascular parkinsonism, and atypical parkinsonian conditions and unusual misdiagnosis included Alzheimer’s disease (AD), DLB, and drug-induced parkinsonism (Tolosa, et al., 2006).
Groundwork studies with a number of radioligands display major loss of DAT binding in PD patients as measure up to controls, it ought to be distinguished that the role of neuroimaging in the degree of difference in diagnosis of PD has not been obviously established (Piccini and Whone, 2004).
It is also renowned that existing progress in the description of the parkinsonian syndromes have led to the development in medical investigative accuracy; though, clinical standard alone are not at all times sufficient to distinguish between idiopathic PD and other parkinsonian syndromes, mainly in the early periods of disease and in atypical appearances (Piccini and Whone, 2004). Consequently, in addition to the growth and execution of diagnostic medical evaluations, there is a call for accessible purpose indicators to help clinicians in the differential analysis of PD (Piccini and Whone, 2004).
Numerous symptoms of PD have the potential to effect neuropsychological test results. In the neuropsychological examination of the PD patient, motor dysfunction must be considered as the cause of impairments on any measure requiring fine or gross motor control. Although PD is first and foremost considered a movement disorder, the high incidence of psychiatric complications suggests that it is more precisely conceived as a neuropsychiatric disease.
Depression, deterioration of mental faculties such as memory, and symptoms of mental illness are common manifestations of unknown cause of PD and are related with poor quality of life, inferior prognosis, as well as caregiver burden (Rihmer et al, 2004). They also noted that depression is one of the most disabling symptoms of PD, with an occurrence of about 40 %; sadly, such depression is often unrecognized and untreated in patients with PD (Rihmer et al, 2004).
Papapetropoulos and Mash (2005) confirmed that psychotic signs are common in patients with PD and take place in at least 20 % of medication-treated patients. Non cancerous visual illusion regularly emerged earlier, while chronic restlessness, bewilderment, hallucination, delusions, malignant hallucinations, and suspicious attitude become more common with disease progression (Papapetropoulos and Mash, 2005).
Almost all anti-parkinsonian medications may create psychotic indications; also, cognitive destruction, increased age, disease duration and severity, depression, as well as sleep disorders have been constantly documented as independent risk factors for their expansion (Rihmer et al, 2004). Even though the accurate cause for the development of disease of psychosis in PD is not fully known, there is some evidence that relations over-activity of the frontward dopaminergic pathway with the participation of other neurotransmitter system imbalances as likely contributors (Lauterbach, 2005).
Dementia takes place in up to 30 % of patients with PD; cognitive impairments involve attentional, decision-making, recollection, and visuospatial dysfunctions (Lauterbach, 2005). Also, Levin and Katzen (2005) confirmed that premature cognitive changes in PD patients are frequently slight and predisposed by factors that act together with the disease development, as well as medication, motor symptoms, and age of disease onset. These factors in spite of adequate details exist that definite cognitive change arises early in the path of PD, It is also noted that this facts does not involve that cognitive insufficiency are persistent during the early stages (Levin and Katzen, 2005).
On the contrary, they are characteristically delicate and often difficult to recognize without proper neuropsychological testing. Decision making function insufficiency are the most regularly reported cognitive troubles and, given that executive ability are a necessary part of many tasks, it go after that subtle complexity may be seen on a wide variety of cognitive measures, mainly in working memory as well as visuospatial dysfunction, two areas that depend a great deal on decision-making skills. While brain disorder and verbal communication processing deficits occur rarely, delicate changes in olfaction and contrast sensitivity have also been frequently observed (Levin and Katzen, 2005).
Neuropsychological Tests In Clinical Trials
Clinical and Regulatory Issues
Psychological testing evaluates a variety of mental abilities and attributes, including accomplishment and aptitude, behavior, and neurological performance (Chouinard, 1993). Psychological testing, including neuropsychological assessment, used a set of uniform tests, whose soundness and dependability have been accepted empirically, they allow for an evaluation of a patient’s ability to think, learn, and memorize and behavioral performance and an psychoanalysis of changes connected to mental or physical disease, injury, or abnormal development of the brain (Grant, 1996).
Standardized tests are controlled under uniform conditions, scored objectively – the procedures for scoring the test are specified in detail – and intended to measure relative performance and test results typically are interpreted with reference to a similar group of people, the standardization, or normative sample (Kovner et al, 1998). Psychological tests are used to deal with a variety of questions about people’s functioning, diagnostic classification, co-morbidity, and choice of treatment approach, for instance, personality tests and inventories assess the thoughts, emotions, attitudes, and behavioral traits that add to an individual’s interpersonal functioning (Gregory, 1999).
The outcomes of these tests conclude an individual’s personality strengths and weaknesses, and could identify definite disturbances in personality, or psychopathology (Leahy, 1998). One type of personality test is the projective personality assessment, which asks a subject to interpret some uncertain stimuli, such as a series of inkblots, the subject’s responses can provide insight into his or her thought processes and personality traits (Gregory, 1999).
Criteria for Neuropsychological Tests
Neuropsychological testing is a subclassification of psychological testing and a well-established method for evaluating patients who demonstrate cognitive or behavioral abnormalities (Blostein et al, 1997). Neuropsychological testing is used when a differentiation between organic versus functional disorders is needed to direct proper therapy (e.g., occupational, physical, or speech and language therapy), predict neuropsychological recovery, or monitor progress (Blostein et al, 1997).
Neuropsychological testing may be necessary for persons with documented neurologic disease or injury (e.g., traumatic brain injury, stroke) when there is uncertainty about the degree of impairment, or when an organic deficit is present but information on anatomic location and extent of dysfunction is required (Hu et al, 1999). An organic deficit is defined as a symptomatic manifestation of structural cerebral or systemic medical pathology, as opposed to being considered psychological or emotional in nature (functional), such testing can also be used to systematically track progress in rehabilitation after brain injury or other neurological disease (Hu et al, 1999).
Motor functions of patients with Parkinson’s disease are determined by its fundamental symptoms: loss of ability to move a body part, shaky, stiffness and disturbed righting impulses. To assess level of disability and rate of its series in Parkinson disease, easy but dependable and reproducible rating scales are necessary. The Unified Parkinson’s Disease Rating Scale (UPDRS) is the gold standard assessment instrument for distinguishing impairments in persons with Parkinson’s disease (PD). Understanding the associations between UPDRS scores and functional capabilities may allow clinicians to improved measures on early physical functioning, longitudinally evaluate disease sequence, and assess the effectiveness of interventions.
Affective disorders (depression and anxiety), cognitive impairment or dementia, and psychosis have long been recognized as part of PD presentation. Depression in patients with PD has a slightly different symptom profile than depression in patients without PD, including higher rates of anxiety, pessimism, suicide ideation without suicide behavior, and less guilt and self-reproach (Leentjens, 2004). Core nonsomatic symptoms of depression (eg, suicide thoughts, feelings of guilt, depressed mood, and anhedonia) discriminate highly between depressed and nondepressed patients with PD, whereas somatic symptoms correlate variably with a diagnosis of depression (Leentjens, 2003).
Patients with PD should be screened regularly for depression. Given time constraints, a brief screening instrument that can be self-administered is recommended. For example, the 15-item Geriatric Depression Rating Scale-Short Form (GDS-15) (Sheikh, 1986) is a brief, yes/no questionnaire that has been validated in PD. A cutoff score of ≥ 5 has the optimal sensitivity and specificity for a diagnosis of depression (Weintraub, 2006), and the instrument is equally valid in older and younger patients with PD (Weintraub, 2007).
A Movement Disorder Society (MDS) task force concluded that for screening purposes, recommended instruments include the Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the GDS-15 and GDS-30. For measurement of severity of depressive symptoms, the task force recommended the HAM-D, the MADRS, and the BDI (Schrag et al, 2007). The HADS and the GDS comprise of limited motor indication evaluation and may, consequently, be most practical in scoring depression severity across a series of PD severity (Schrag et al, 2007).
Implications for treatment by Neuropsychologist
With so many advantages clinicians must get together neuropsychological discussion for a variety of motives. When a patient is representing minimal or doubtful mental shortfall clinicians may call for a more in depth assessment. By turning to neuropsychological tests a more accurate evaluation can be determined concerning whether the patient has irregularities or is just describing regular mental insufficiency that may arise under conditions such as stress or aging. It is also helpful for clinicians to use neuropsychological tests when they require deciding the number of discrepancy the patient demonstrates.
This is particularly supportive in recognizing whether the patient’s disorder is getting better or getting worse. When it is essential to determine a patient’s power and limitation neuropsychological tests may assist to recognize a treatment or management arrangement to help in the patient’s recuperation process. Neuropsychological tests can even give an in depth outline of the patients disorder that can be used next to other data to help the course of analysis.
Finally, when a patient may have to undergo epilepsy surgery neuropsychological evaluations are important. The use of neuropsychological evaluations should depend on the condition of the patient. Neuropsychological assessments should also remain supple because there are many features that can add to a tests result. When a clinician is choosing a test to direct and understand they should keep a number of factors in mind. It is also significant for a clinician to distinguish that using neuropsychological assessments alone is not adequate enough to base a patient’s evaluation on. Additional medical and laboratory tests should be used along with neuropsychological tests to give a sufficient assessment of a patient.
PD is a progressive neurodegenerative disorder demonstrated by a wide range of motor and non-motor characteristics. The normal sequence of PD is changeable but is frequently more rapid in patients with late onset and with the PIGD form of PD. In a wide-ranging analysis of the literature, the consistent death ratio has been accounted to vary between 1 and 3. Since there is no ultimate diagnostic examination for it, clinicians necessitate methodical information of the clinical expression of PD to help them in differentiating it from associated disorders.
Future research may find out disease specific biomarkers permitting for its differentiation from other neurodegenerative disorders. Not simply will such testing be helpful for identifying the disease in concerned persons, it will be practical for recognizing family members or populations at risk, therefore providing a chance to begin neuroprotective treatment at an asymptomatic phase.
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