Case-control study New Jersey, USA Case-control study New Jersey, USA Case-control study French West Indies
50 cases from 100 hospital controls neurologists and tertiary center
75 cases from tertiary 75 neurology outpatients center (91 unmatched) excluding neurodegenrative diseases (106 unmatched) 31 PSP and 30 atypical 65 hospital controls parkinsonism from neurology dept.
Case-control study Mainly Italy but also 55 cases from tertiary Austria and Germany centers
134 relatives of patients with non-neurological controls
1991 Case-control study USA
60 cases from NINDS, 60 controls from spouses, newsletters, or private friends, and volunteers doctors
2000 Case-control study Mainly Italy but also 75 cases from tertiary
Austria and Germany centers
134 relatives of patients with non-neurological controls
Finished high school 3.1, finished college 2.9, rural residence 2.4 At least 12 years education 0.35 (0.12 to 0.96); no difference by rurality Fruit or herbal tea 4.35, (1.25 to 15.2) for PSP, 4.27, (1.22 to 14.9), for atypical parkinsonism
Smoking OR 0.91 (0.42-1.98); no dose-response
College education 0.39 (0.16-0.90); significant associations with metal dust and fumes 14.8, pesticides 5.8, plastic monomers and addditives 5.3 Smoking 0.56 (0.29-1.06); dose-response effect cases represent PSP or not. Only one patient in their study had a neuropathological examination, which showed changes seen in amyotrophic lateral sclerosis (ALS). It is not clear whether this was one of the PSP, PSP and ALS, or unclassifiable patients. Circumstantial evidence that the PSP-like syndrome may be PSP comes from a neuropathological study of five PSP patients from Guadeloupe, all of whom consumed large amounts of either tropical fruits or herbal teas. All these cases had neuropathologically confirmed PSP, with four-repeat tau deposition.
Although this study provides a model for the role of dietary factors or a neurotoxin, the specific dietary components are fairly unique to this population and can provide clues to other substances only by analogy. Two case-control studies in New Jersey, conducted by the same research group 8 yr apart tried to identify a wide range of possible factors. The first (24), in 1988, compared 50 PSP patients (Golbe diagnostic criteria) in a tertiary-referral center with 100 age- and sex-matched inpa-tients with non-neurological disorders. It examined 85 potential factors including educational attainment, family history, and toxin exposures. In an attempt to improve the quality of information and possibly reduce recall bias between control and patient groups, questionnaires were administered to surrogate respondents only (the patient's spouse or offspring or sibling). This may have led to reducing any true association as relatives may not have been aware of all occupational exposures resulting in nondifferential misclassification toward the null. The only significant finding was that PSP patients were more likely to have completed high school, completed 4 yr at college, and live in an area with a population of less than 10,000 as an adult. It is unsurprising that out of 85 hypothesis tests, 3-4 tests were significant by chance at the 5% level (type I error). These findings could also be explained, as discussed in the paper, by selection bias; patients identified from tertiary referral centers are more likely to have a higher educational level and come from a wider catchment area than inpatients with acute medical problems from the local community. These findings failed to replicate in the follow-up study in 1996 (25). On this occasion, to avoid selection bias, non-neurodegenerative controls were drawn from the same pool of neurology outpatient referrals as the patients. Using a self-completed postal questionnaire, the study examined factors that neared statistical significance in the previous study. Now, PSP patients were less likely to have completed 12 yr at school, but no other factors were significant. The authors hypothesized that this may be a proxy for either lower nutritional status, somehow leading to a propensity to develop PSP, or possibly exposure to an unknown neurotoxin in early life. However, it is unclear how representative was the sample of controls. Given the severity of PSP, it is likely that all cases will eventually be referred for a neurological opinion, though not always to a tertiary specialist center. However, other neurological conditions, e.g., headaches, sciatica, etc., may be referred to a wide variety of other clinicians. Those reaching a tertiary center may be biased toward a higher educational level.
Since smoking shows a negative association with Parkinson's disease, Vanacore and colleagues examined this factor among PSP patients (26). The study recruited 55 PSP and 134 control subjects. The control subjects were healthy relatives of patients with non-neurodegenerative diseases. Any further information about control selection was not given nor were the response rates reported. Since smokers are likely to be overrepresented in any randomly selected patient cohort, there is the possibility that controls were more likely to be relatives of patients who smoked. This bias would tend to show an inverse association with PSP but in fact there was little evidence of any association, though the wide 95% confidence intervals mean it is not possible to exclude even a halving of risk as seen with PD.
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