Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis
Introduction
Despite a vast amount of experiential and anecdotal data from practicing neurologists indicating distinct variability in disease expression for idiopathic Parkinson's disease (IPD), there is no universally accepted or standardized measure for clinical classification into disease subgroups. Yet, converging evidence from clinical, cognitive, and neuropathological sources has provided compelling support for the existence of distinct subtypes in Parkinson's disease (PD).
In their 1967 landmark study of disease progression, Hoehn and Yahr [1] initially described the marked diversity exhibited among these patients. Specifically noted was that “the clinical picture of one may be dominated by tremor, of another by rigidity or akinesia” (p. 433). Other studies have examined such factors as age of symptom onset [2], levodopa responsiveness [3], [4], familial history [5], tremor predominance [1], [6], dementia [7], [8], and depression [9] in attempts to establish prototypical subtypes that have similar clinical presentation, disease progression, and prognosis.
The distinction between tremor-dominant (classic) and akinetic-rigid PD types has been described by some researchers as “benign vs. malignant” [3], referring to clinical course and disease progression. Others have proposed subgroups based on predominant clinical features of the disease (i.e. “tremor vs. akinetic-rigid”) [5]. Data from one of the largest clinical studies conducted to date has provided empirical support for PD subgroup differences [10]. Results showed that bradykinetic PD patients exhibited more rapid deterioration and greater cognitive impairment than patients with tremor-dominant PD.
Neuropathology studies of autopsy-verified PD cases have corroborated clinical reports of distinct PD subgroups. In one series, patients with marked akinesia and rigidity revealed higher neuronal loss in the locus ceruleus (LC), medial, and lateral substantia nigra (SNM, SNL), and more severe gliosis, extraneuronal melanin deposits, and neuroaxonal dystrophy in the substantia nigra compared to tremor-dominant cases [11]. A severe reduction in dorsal raphe (serotonin-producing cell bodies) neuronal density was observed in clinically depressed PD patients. In another series, a preponderance of tremor-onset cases had Lewy body disease, while the majority of cases with postural instability and gait disturbance (PIGD) had other forms of pathology [12]. These studies indicate that the subgroups are characterized by distinct neuropathological lesions and may represent distinct clinical–biochemical entities within PD.
The initial aim of the current project was to develop a standardized approach in the clinical evaluation of PD patients that would provide an objective method of classifying patients into distinct disease subtypes. Based on a modification of Jankovic et al. [10] procedure, a rating system was developed to evaluate multiple clinical indices (such as tremor, rigidity, hand movements, arising from a chair, posture, gait and bradykinesia), using the universally utilized and validated [13], [14] Unified Parkinson's Disease Rating Scale (UPDRS, [15], [16]). For classification purposes, a numerical ratio value was derived from a patient's mean tremor score and mean akinetic-rigid score, in order to identify tremor dominant, akinetic-rigid, or mixed PD subtypes.
The second objective of the study was to examine differences in neurotransmitter profiles between the PD subgroups and non-PD neurological control patients. The proposed classification system was retrospectively applied to a consecutive series of PD patients who subsequently underwent neurosurgical intervention (i.e. posteroventral pallidotomy or PVP) for their disease. It was hypothesized that the clinical PD subtypes would have different biochemical profiles and could be further differentiated from non-PD controls. High pressure liquid chromatography (HPLC) analysis of ventricular cerebrospinal fluid (V-CSF) was used to determine if the subtypes as classified by the proposed scheme would have different profiles of neurotransmitter activity when analyzed under similar conditions and compared to controls as well as among PD subgroups.
Section snippets
Participants
The target sample consisted of 30 clinically confirmed idiopathic PD patients (17 males, 13 females) with medically refractory disease, who received neurosurgical intervention for their PD symptomatology. These patients ranged in age from 40 to 83 years of age, with a mean age of 61.37 (SD=10.28) years and a mean disease duration of 9 years (range=5–27 years). All patients were treated with levodopa in the form of varying doses of regular carbidopa/levodopa and/or sustained-release
Results
Preliminary analysis of the demographic characteristics of the sample revealed no statistically significant differences in mean age or disease duration among PD subtypes; however, the mixed PD subgroup was significantly older than non-PD neurological controls (F=3.09, P<0.05).
A scattergram of the tremor and akinetic-rigid scores for each PD patient is presented in Fig. 1. In this figure, the Y-axis represents a patient's mean tremor score and the X-axis represents a patient's mean
Discussion
The development of a rating system designed to identify clinical subtypes within the PD population has important implications in our understanding and management of these patients. Using the proposed classification system to group PD patients into primary clinical subtypes, validation of the schema was conducted by evaluating differences in biochemical profiles between PD subgroups and non-PD neurological controls. The results are consistent with clinical and empirical observations, indicating
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