Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis

Abstract

The current study presents preliminary data regarding the development and validation of a rating system designed to classify PD patients into clinical subgroups. Using portions of the Unified Parkinson's Disease Rating Scale, a ratio value was derived, yielding three patient subtypes: a tremor-dominant group (T), an akinetic-rigid group (AR), and a mixed group (MX). Validation of the schema was conducted by grouping PD surgical candidates into specific disease subtypes and evaluating differences in neurotransmitter profiles among disease subtypes and non-PD neurological controls. High pressure liquid chromatography analysis of ventricular cerebrospinal fluid indicated 5-hydroxyindoleacetic acid was significantly lower in the AR and MX groups compared to non-PD controls; whereas, glycine was significantly higher in the AR group compared to the T, MX, and control groups. The results suggest that an operational approach can be utilized to differentiate between PD subtypes with distinct neurochemical profiles.

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.