As an age-related neurodegenerative disorder, Parkinson's disease (PD) affects about one million Americans, and these numbers are expected to grow as the population ages. Although the etiology is known in a small percentage of genetically related cases, the disorder is largely idiopathic, and likely involves interactions of the genome and the environment [1]. Three recent case-control studies [2]–[4] suggest that higher serum cholesterol levels may be related to lower prevalence of PD. Three independent prospective studies provided further support for the hypothesis that higher serum cholesterol may be associated with a lower future risk of PD [5]–[7]. A fourth prospective study whose PD case identification was based on a Finnish National Insurance Register that entitles patients to medication free of charge, however, offered a contradictory finding [8]. Although the findings are still controversial, the overall evidence favors an association between higher cholesterol and lower PD occurrence, suggesting a beneficial role of higher serum cholesterol in the PD process. No study, however, has examined the relationship between serum cholesterol and PD progression. In this study, we tested the hypothesis that higher serum cholesterol levels may be associated with slower progression of PD by analyzing the data collected from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial.

The overall mean cholesterol level was 216 mg/dL (range 100–355) (Table 1). Participants in the higher cholesterol quintiles were more likely to be female (p<0.001). Population characteristics were otherwise similar across quintiles of baseline cholesterol concentrations. Of all patients, only nine reported the use of cholesterol-lowering medications at baseline, and two of them indicated statin use. The cholesterol levels did not vary significantly by treatment group (deprenyl = 217.6 mg/dL, α-tocopherol = 213.3 mg/dL, both = 213.1 mg/dL, placebo = 214.3 mg/dL, p = 0.64).

Higher cholesterol levels tended to be associated with lower risk of reaching the primary endpoint with a borderline statistical significance (Tale 2, p for trend = 0.09). Compared to the lowest quintile, the HRs (95% CI), for each higher quintile (in ascending order) are 0.83 (0.59–1.16); 0.86 (0.61–1.20); 0.84 (0.60–1.18); and 0.75 (0.52–1.09) respectively. The HR for each standard deviation (SD) increase = 0.90 (0.80–1.01, p = 0.09). The subgroup analysis in males showed a statistical difference between the highest cholesterol quintile and the lowest in reaching the primary endpoint [HR = 0.59 (0.38–0.93), p = 0.02]. The HR for each 1 SD increase in males was 0.88 [(0.77–1.00), p = 0.05]. No such relationship was seen in females (Table 2).

The annual rates of change in UPDRS scores are highest in the PD subjects with the lowest quintile of baseline total serum cholesterol (Table 3), but there were no statistically significant differences in any group. Similarly, the results in Table 4 show no associations between baseline total cholesterol and either the time to death or the time to freezing of gait.

Prior literature has suggested that lower cholesterol may be associated with higher risk of PD [2]–[7], but there have been no studies to determine if there also is an association with faster PD progression. The statistical analysis of the relationship between baseline serum cholesterol and PD progression, was, however, borderline if based on p values of two tail t-test (p = 0.09 for whole cohort, 0.05 for male cohort). If one, however, assumes that a unidirectional outcome was predicted from the prior clinical data [2]–[7] and the study was to provide pilot data for pursuing future studies to test the hypothesis, a one-tailed analysis is justified [16] and makes the results significant for the group as a whole (p = 0.04), as well as for just males (p = 0.02). This study provides the first preliminary evidence that lower total serum cholesterol also may be associated with modestly faster progression of PD symptoms, supported the need for further investigation into the relationship between cholesterol and PD progression.

The question of whether low cholesterol contributes to faster PD progression, is merely a marker of more advanced pathology of PD, or is simply an epiphenomenon, cannot be addressed from this study. Cholesterol is involved in a plethora of critical biological functions ranging from cellular repair or degeneration [17]–[22] to being a neurosteroid precursor [23]–[26]. Whereas cholesterol may affect PD etiology or clinical progression, it is also conceivable that lower cholesterol could be a mere marker for a more advanced pathology of PD. Thus, understanding the nature and underlying mechanisms of the associations between lower cholesterol and increased PD risk or faster progression may have a profound influence in understanding key aspects of sporadic PD. Intriguingly, potential beneficial roles of higher cholesterol in other neurodegenerative disorders also have been implied. Hyperlipidemia was recently found to be a significant prognostic factor for survival of patients with amytrophic lateral sclerosis (ALS) [27], and lower cholesterol has also been suggested to be related with multisystem atrophy [28]. While this recent evidence is preliminary, it underscores the importance of understanding the role of cholesterol in neurodegenerative diseases. If the association turns out to be causal, there may be public health implications because aggressively lowering cholesterol has been advocated based on possible cardiovascular benefits.

An important strength of this current study is that it was initiated with primary endpoints evaluated mostly in the pre-statin era with less than 0.3% of the participants reporting statin usage at baseline. Statins are now commonly and sometimes aggressively used to lower serum cholesterol for cardiovascular benefits [29], [30]. Although the epidemiological data are preliminary and inconsistent, statin use has been hypothesized to be neuroprotective against PD [31]–[33]. Because statins effectively decrease plasma cholesterol and because statins may modify PD pathogenesis, it is difficult to determine the independent effect of chronic levels of plasma cholesterol on PD progression among populations with prevalent statin use. Another dataset of potential interest was the PRECEPT study, a neuroprotection trial conducted by PSG investigators that began in 2002 [34]. In PRECEPT, there were significant increases of statin usage with each lower quintile of total serum cholesterol levels (i.e., the percentage of the PD subjects reported statin usage from lowest to highest quintiles was: 37.6%, 26.4%, 19.4%, 10.8%, and 6.8% respectively). No significant association (unpublished data) was found between baseline cholesterol levels and PD progression (i.e., time to need dopaminergic therapy), but the analysis is confounded by the high degree of use of cholesterol-lowering medication (i.e., the measured cholesterol levels do not reflect premorbid levels). The fact that, in the current study, our primary end point was evaluated before the widespread use of statins largely eliminates these potential concerns.

In addition to sample size, the current study has other limitations. Total cholesterol was not measured in the fasting condition, and cholesterol was not fractioned as HDL and LDL-components. Moreover, and as noted earlier, the limited sample size particularly impacts the FOG analysis. Nonetheless, this is the first suggestion that there is an association of low cholesterol and faster PD progression, and is consistent with prior reports of an association with higher risk of PD. Since these measures are often part of routine clinical assessment, it may be that future studies in large groups of PD patients should include a fasting cholesterol measurement, and incorporate this and the use of statins and other cholesterol lowering drugs into data analyses. If these preliminary findings are supported, than basic studies of the potential underlying mechanism(s) would be warranted.