The cause of PSP is unknown but it is hypothesized that genetic and/or environmental factors contribute to its development (52,53) (Fig. 3). Environmental and genetic factors have also been linked to other neurodegenerative disorders.
PSP is associated with a specific form of the tau gene (H1 tau haplotype) (5,54,55) (see Chapters 5 and 9). However, since the H1/H1 genotype is present in approx 90% of patients with this disorder, and also in approx 60% of healthy Caucasians, it is unclear whether inheritance of the H1/H1 tau genotype represents a predisposition to develop PSP (requiring other environmental or genetic factors), or whether a relatively rare mutation with low penetrance (rather than an inherited susceptibility variant) could contribute to the abnormal tau aggregation present in this disorder.
CBD is also associated with the inheritance of the H1 haplotype (54,55). The observation that coding and splice-site mutations in the tau gene cause FTDP-17 demonstrates that tau dysfunction is sufficient to induce neurodegeneration (44,56-58). The parallels between FTDP-17 and PSP/CBD also include the fact that there are FTDP-17 patients with defined tau mutations (e.g., P-301, N279K) who share many clinical and pathologic features with PSP and CBD (59-61) such as selective deposition of 4-R tau. However, because highly penetrant tau mutations are not found in PSP and CBD, it is likely that other genetic or environmental factors contribute to the development of these disorders. Litvan et al. recently showed in a pilot study that H1 haplotype dosage does not influence age of onset, severity, or survival of PSP patients (5) in contrast to what is observed with ApoEe4 in AD. It is likely that differential environmental or genetic factors may lead to different cell vulnerability, phenotypes, and rate of disease progression observed in PSP patients. Whether the rarely reported familial cases of PSP (62,63) are owing to unidentified FTDP-17 mutations or they are a result of non-tau mutated genes, is currently the subject of investigation.
Several laboratories have suggested that mitochondrial abnormalities (64-66) and lipid peroxidation may play a role in the neurodegeneration occurring in PSP (67-71). Albers et al. measured tissue malondialdehyde (MDA) levels in the subthalamic nucleus and cerebellum from brain tissue of 11 PSP and 11 age-matched control cases using sensitive HPLC techniques, and found a significant MDA increase in the subthalamic nucleus, but not in the cerebellum, of the PSP patients (69). Significant increases (+36%) were also found in tissue MDA levels in the superior frontal cortex of 14 PSP patients as compared with controls, and significant decreases (-39%) were also found in the a-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio (70). Increased oxidation has been also found in the substantia nigra of PSP patients. These findings suggest that lipid peroxidation may explain regionally specific neurodegeneration in PSP. Further, Odetti et al. (71) showed that lipoperoxidation is selectively involved in PSP and hypothesized that intraneuronal accumulation of toxic aldehydes may hamper tau degradation leading to abnormal aggregation. It is likely that irrespective of the primary cause of PSP, the onset of oxidative stress is a common mechanism by which neuronal death occurs, and one that contributes to disease progression.
Inflammation is thought to play a role in the etiopathogenesis of PSP because of strong evidence that in PSP there is activated glia (72-76) and that there may be augmented complement activation in the brain (higher CSF levels of C4 in PSP compared to controls and PD) (77). Moreover, active glial involvement in PSP is as (or more) severe than that found in AD (54). Inflammation has also been demonstrated in other neurodegenerative disorders. In AD, activation of the complement cascade and accumulation and activation of microglia (78,79) have also been reported. Although there is limited information about a decreased inflammatory reaction after treatment with antiinflammatory medication in autopsy-confirmed AD cases (79,80), several epidemiologic studies have shown that antiinflammatory agents may delay the onset and slow the progression of AD (81-83).
Only a few case-control studies have been conducted in PSP and the findings reported have limited value because of the small sample size of the studies. Two case-control studies from the same institution resulted in conflicting conclusions on the role of education as a risk factor for PSP (38,84). The authors attributed this disparity to methodologic differences in control selection (84). The possibility that lower educational attainment may be a proxy for poor early-life nutrition or exposure to neurotoxic substances or that alternatively, subtle cognitive changes of PSP begin early in life so as to impair intellectual or educational motivation, have been hypothesized (84). Davis et al. found that cases of PSP had a significantly higher educational level than controls in two of three categories tested (odds ratio [OR] 3.1 for completing high school, and 2.9 for completing college,p < 0.05) (38), whereas Golbe et al. found that patients with PSP were less likely to have completed at least 12 yr of school (OR = 0.35) (84).
On the other hand, recent studies in the French West Indies suggest that environmental factors may be relevant for developing PSP. Caparros-Lefebvre et al. (85) reported an unusually high frequency of patients with an atypical parkinsonian syndrome (postural instability with early falls, L-dopa unresponsiveness, prominent frontal lobe dysfunction, and pseudo-bulbar palsy) over the past 5 yr in the French West Indies. This new focus of atypical parkinsonism has been linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines [TIQ], acetogenins, rotenoids). In an initial case-control study, Caparros-Lefebvre et al. (86) reported an association with consumption of tropical fruits (pawpaw) or herbal teas (boldo) in 31 patients with PSP and 30 patients with atypical parkinsonism compared to controls (OR = 4.35). More recently, the authors reported that from 220 patients consecutively evaluated at the Guadeloupe University Hospital, they found 58
with probable PSP, 96 with undetermined parkinsonism, 50 with PD, 15 with ALS and parkinsonism, and 1 with probable MSA. This cluster of cases seem to have a tauopathy closely related to PSP. Neuropathological examination of three patients who died and were homozygous for the H1 tau haplotype showed an accumulation of four-repeat tau proteins predominating in the midbrain (85). There is evidence that TIQs are potentially neurotoxic (87,88). Injections of TIQs have caused parkinsonism in mice (89-91) and in primates (92-94). In addition, cellular studies showed that TIQs exert a direct toxicity to dopaminergic neurons through inhibition of complex I enzymes, a mitochondrial mechanism similar to that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or roten-one exposure (95,96). It is unlikely that PSP patients seen in the United States or Europe are past consumers of the tropical fruits and herbal teas that have been linked to PSP in Guadeloupe. However, TIQs have been found in foods that are common in the Western diet, specifically, in cheese, milk, eggs, cocoa, and bananas (97,98). Although the amounts of TIQs in these foods vary, they may accumulate in the brain over many years (97). There have also been reports of other toxins causing atypical parkinsonism. There is some evidence of an environmental effect in Lytico-Bodig disease (99) and ecological correlations support the cycad hypothesis (100,101).
Environmental exposure to organic solvents has also been reported in patients with PSP (102,103). Petroleum waste ingestion has been linked to parkinsonism in a 20-yr-old man (104). N-Hexane has been shown to induce parkinsonism in rats (105), and was linked to parkinsonism in a 49-yr-old Italian leather worker (106). Although PSP patients were not found to have an association with any occupation or toxin exposure in the two previous case-control studies (38,84), these studies were not powered to test this hypothesis.
A possible role for traumatic brain injury (TBI) as a risk factor in the development of 4R-tauopathies such as PSP is supported by several observations. First, it is well known that repetitive TBI induces the formation of neurofibrillary tangles (107), which are found in PSP. Second, post-traumatic parkinsonism may occur following cumulative head trauma in contact sports and infrequently after a single severe closed head injury (108,109). However, it is unclear whether TBI should be considered a risk factor in the pathogenesis of PD (110). Third, several epidemiologic studies have demonstrated that TBI is a risk factor for developing another tauopathy, AD (111-113), although controversy exists over the extent to which TBI and genetics contribute to the development of AD. A recent large cross-sectional multicenter study of first-degree relatives of AD patients suggest that the influence of TBI on developing AD is greater among persons lacking APOE-e4 compared with those having one or two e4 alleles (113). These findings were confirmed in a retrospective study that evaluated two autopsy-confirmed cohorts of patients with AD with known APOE-e4 genotype (114). On the other hand, two recent large European prospective clinical epidemiologic studies suggest that a history of TBI, with or without an association with APOEe4, is not a risk factor for developing AD (115,116), although major or many TBIs may increase the risk of cognitive decline (117). Finally, a large number of experimental animal studies support the role of TBI in the onset or progression of AD. Regrettably, a previous epidemiologic study in PSP had limited power to study this issue but note that it found high ORs for boxing (4.0), TBI with loss of consciousness (2.4), and TBI with memory loss (1.8), although none of them reach statistical significance (38).
Davis et al. found that heavy coffee drinking (>5 cups/d) and cigarette smoking were inversely associated with PSP, but that the results of their case-control study were statistically insignificant (38). Vanacore et al. found no difference in tobacco use between PSP cases and controls (118). The number of cases in both PSP studies, however, was small (50,55). Risk factors that occur with low frequency in the population may not be detected, thus resulting in type II error. These findings contrast with those in PD. An analysis from the Honolulu-Asia Aging Study based on a large sample size suggest that midlife coffee consumption is significantly inversely associated with PD independent of the effect of tobacco use (119). Similarly, a significant inverse association between heavy coffee drinking (>5 cups/d) before or at age 40 yr and PD (120) and that tobacco use is inversely associated with PD, has been tested in several studies (121).
The role of hypertension (HTN) in PSP remains controversial. Dubinsky and Jankovic proposed a "vascular" etiology for some of the cases diagnosed as clinical PSP (122). They found that 19/58 PSP patients (32.8%) had radiological evidence of cortical, subcortical, or brainstem strokes, compared with 25/426 (5.9%) of PD patients (p < 0.001). The same group of investigators (123) found that 30/ 128 (23.3%) of PSP patients satisfied the criteria for vascular PSP. However, there have been few autopsy-confirmed cases of exclusively vascular PSP. Frequently, PSP associates with strokes or other neurodegenerative diseases (124). Two studies looked at the presence of presymptomatic HTN in patients with PSP (125,126). Ghika et al. excluded clear-cut cases of vascular parkinsonism by omitting cases with obvious multilacunar state on computed tomography (CT) or magnetic resonance imaging (MRI), severe hypertensive leukoencephalopathy, Binswanger disease, pseudo-PSP owing to small vessel disease, and vascular dementia. They found that the prevalence of presymptomatic HTN in patients with clinically diagnosed PSP was 34/42 (81%). Because the vascular cases were excluded, they proposed that HTN may be the first symptom of PSP, arising from degeneration of adrenergic nuclei in the brainstem. However, Fabbrini et al. (125), and a previous case-control study conducted by Davis et al. (38), found no increased frequency of HTN in PSP patients. Further studies are needed to evaluate whether HTN is simply acting as a risk factor for vascular parkinsonism.
Whether the factors discussed provide a clue for the pathogenesis of 4R-tauopathies, are applicable to a possible protective mechanism, or whether the epidemiologic data support the notion that different risks factors may be associated with different groups of neurodegenerative disorders, needs to be further investigated. Although the literature on PSP is definitely limited, it is reasonable to consider that there may be different risk factors for PSP than for the other neurodegenerative parkin-sonian disorders.
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.