The assessment of PD is difficult, because it is expressed variably in an individual patient at different times and it is influenced by emotional state, response to medication, and other variables. Moreover, there is a marked interpatient variability of symptoms and signs. To study this heterogeneity and to determine possible patterns of clinical associations, we analyzed the clinical findings in 334 patients with PD and identified at least two distinct clinical populations of parkinsonian patients (104). One subtype was characterized by a prominent tremor, an early age at onset, and a greater familial tendency. Another subtype was dominated by postural instability and gait difficulty (PIGD) and was associated with a greater degree of dementia, bradykinesia, functional disability, and a less favorable long-term prognosis.
These findings are supported by the results of an analysis of 800 patients with untreated PD included in the multicenter trial Deprenyl and Tocopherol Antioxida-tive Therapy of Parkinson's Disease (DATATOP). The PIGD group had greater occupational disability and more intellectual impairment, depression, lack of motivation, and impairment in activities of daily living than a corresponding group of patients with tremor-dominant PD (15). The investigators concluded that patients with older age of onset and a presentation with PIGD and with bradykinesia are more likely to have a more aggressive course than those with early symptoms dominated by tremor (105). In order to determine the overall rate of functional decline and to assess the progression of different signs of PD, we prospectively followed 297 patients (181 males) with PD for at least three years (105). Data from 1731 visits, over a period of an average of 6.36 years (range = 3-17 years), were analyzed. The annual rate of decline in the total Unified Parkinson's Disease Rating Scale (UPDRS) scores was 1.34 units in the on state and 1.58 units in the off state. Patients with older age at onset had a more rapid progression of disease than those with younger age at onset. Furthermore, the older onset group had significantly more progression in mentation, freezing, and UPDRS activities of daily living subscores. Handwriting was the only component of the UPDRS that did not significantly deteriorate during the observation period. Regression analysis of 108 patients, whose symptoms were rated during the off state, showed a faster rate of cognitive decline as age at onset increased. The slopes of progression in UPDRS scores, when adjusted for age at initial visit, were steeper for the PIGD group of patients as compared to the tremor-dominant group. These findings, based on longitudinal follow-up data, provide evidence for a variable course of progression of the different PD symptoms, thus implying different biochemical or degenerative mechanisms for the various clinical features associated with PD. Hence, PD should be considered a syndrome with characteristic patterns of symptoms, course, response to therapy, and different etiologies. The different subsets of PD may have a different pathogenesis and even a different genetic predisposition.
Longitudinal studies of PD progression utilizing imaging ligands targeting both dopamine metabolism ([18F]DOPA) and dopamine transporter density (P-CIT) using both PET and single photon emission CT (SPECT), respectively, have demonstrated an annualized rate of reduction in striatal [18F]DOPA or [123I]P-CIT uptake of about 6% to 13% in PD patients compared with a 0% to 2.5% change in healthy controls (106). With improved methodology of P-CIT SPECT scans, the annualized rate of decline is now estimated to be 4% to 8% (107). These functional imaging studies are consistent with pathological studies, showing that the rate of nigral degeneration in PD is 8- to 10-fold higher than that of healthy age-matched controls. Several studies have suggested that the rate of progression of PD may not be linear and that the disease progresses more rapidly initially and the rate of deterioration slows with more advanced disease, arguing against the "long-latency" hypothesis for a presymptomatic period in PD (108,109).
The accurate and reliable evaluation of motor dysfunction is essential for an objective assessment of the efficacy of potentially useful drugs. Various mechanical, electrophysiologic, and clinical methods have been utilized to measure the motor findings in PD objectively. Some of the techniques are designed to measure the frequency, amplitude, force, velocity, acceleration of contraction, and other quantitative parameters of the abnormal movement. However, such measurements may have little relevance to the actual functional disability of the patient.
In assessing the motor symptoms and signs of PD, two approaches have been used, both of which strive to quantify the motor findings (77). One method utilizes neurologic history and an examination with subjective rating of symptoms, signs, and functional disability, and the other method utilizes timing of specific tasks or neurophysiologic tests of particular motor disturbances. Although the latter method is considered to be more objective and scientific, it is not necessarily more accurate, reliable, or relevant than the clinical rating. However, both approaches have certain advantages and disadvantages and, when combined, may provide a useful method of assessing the severity of the disability and the response to therapy.
Most of the subjective methods of assessment of parkinsonian disability utilize rating scales of various symptoms and disabilities. The most widely used method of staging PD is the Hoehn and Yahr scale (110). Although this staging scale is useful in comparing populations of PD patients, it is relatively insensitive to changes in the clinical state. Therefore, the Hoehn and Yahr scale is not useful in monitoring the response of individual patients to therapy.
Thus, it is important that the severity of the disease is objectively assessed in the context of the individual's goals and needs. Although a variety of neurophysiologic- and computer-based methods have been proposed to quantify the severity of the various parkinsonian symptoms and signs, most studies rely on clinical rating scales, particularly the UPDRS (111-114; see Appendix 1). In some studies, the UPDRS is supplemented by more objective timed tests such as the Purdue Pegboard or movement and reaction times (19). There are also many scales, such as the Parkinson's Disease Questionnaire-39 and the Parkinson's Disease Quality of Life Questionnaire, which assess quality of life (115). When a particular aspect of parkinsonism requires more detailed study, separate scales should be employed, such as tremor scales or the Gait and Balance Scale (116). Also, it is important that when performing the UPDRS, the instructions are followed exactly. For example, one study of 66 pull tests, part of the UPDRS used to assess postural instability (117), performed by 25 examiners showed marked variability in the technique among the examiners and only 9% of the examinations were rated as error-free (118).
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