Risk factors for idiopathic Parkinson disease http://yassermetwally.com http://yassermetwally.ney

1. Risk factors for idiopathic Parkinson disease
The author: Professor Yasser Metwally
http://yassermetwally.com
INDEX
 Introduction
 Anti-inflammatory drugs and the Risk of Parkinson Disease
 Uric acid and the risk for Parkinson disease
 Vitamin D and Vitamin E and Vitamin C and the risk for Parkinson disease
 Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease
 Cigarette smoking and the risk for Parkinson disease
 Rural residency and the risk for Parkinson disease
 Type 2 diabetes and the risk for Parkinson disease
 The metabolic syndrome and the risk for Parkinson disease
 Other risk factors for Parkinson disease

2. INTRODUCTION
December 7, 2011 — Two environmental factors are recognized to lower the risk for PD, cigarette
smoking [14] and coffee drinking. [15] The mechanisms through which they can reduce risk are not
known. Coffee drinking appears more protective for men, and so it is possible that there may be an
interaction with endocrine factors. A study in PD has also shown that use of a nonsteroidal anti-
inflammatory drug 2 or more times per week can produce a 45% lower risk for PD.[16] Animal and
epidemiologic studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the
incidence of Parkinson disease (PD).
Initiation of any antidepressant therapy was associated with a higher risk of PD in the 2 years after
the start of treatment, which suggests that depressive symptoms could be an early manifestation of
PD, preceding motor dysfunction. [31]
High uric acid levels may be associated with a reduced risk for PD.[17] Significant head injury
increases the risk for PD in later life.[18,19] The effects of physical activity, estrogen status (despite
the male preponderance for PD), and diet on PD risk remain uncertain.
There are, in addition, references in the literature to a range of occupational and environmental
exposures that have variably been associated with a modest increased risk for PD, but their
relevance to the majority of PD patients remains uncertain. These include exposure to solvents [29]
and heavy metals, which may, for instance, in the case of copper cause mitochondrial dysfunction
and Wilson's disease, [20] an important differential diagnosis of PD.
 Anti-inflammatory drugs and the Risk of Parkinson Disease
Anti-inflammatory drugs may prevent Parkinson disease (PD) by inhibiting a putative underlying
neuroinflammatory process. Animal and epidemiologic studies suggest that nonsteroidal anti-
inflammatory drugs (NSAIDs) decrease the incidence of Parkinson disease (PD). Miguel, et al, 2006
[30] studied 1,258 PD cases and 6,638 controls from the General Practice Research Database. The
odds ratios (95% CI) for ever vs never use were 0.93 (0.80 to 1.08) for nonaspirin NSAIDs, 1.29 (1.05
to 1.58) for aspirin, and 1.16 (1.00 to 1.35) for acetaminophen. Nonaspirin NSAID use was
associated with a higher risk in women and a lower risk in men.

3.  Uric acid and the risk for Parkinson disease
Oxidative stress contributes to dopaminergic neuron degeneration in Parkinson's disease. Urate, a
potent antioxidant, could be neuroprotective. MG Weisskopf et al. [33] suggested that high plasma
urate concentrations may decrease the risk of Parkinson's disease, and they raised the possibility
that interventions to increase plasma urate may reduce the risk and delay the progression of
Parkinson's disease.
 Vitamin D and Vitamin E and Vitamin C and the risk for Parkinson disease
o Vitamin D
Vitamin D may protect against Parkinson's even though the mechanism is not understood, although
there is limited evidence from cell-based and animal models that vitamin D may prevent the loss of
dopaminergic neurons. High serum levels of vitamin D is associated with reduced risk for parkinson
disease. Individuals with higher serum vitamin D concentrations showed a reduced risk of Parkinson
disease. [34]
The sudy led by Paul Knekt and colleagues [34] at the National Institute for Health and Welfare,
Finland, examined levels of vitamin D in the blood of 3,173 Finnish men and women aged 50 to 79
determined to be free of Parkinson's disease at the start of the study. The researchers then
examined the incidence of Parkinson's disease in these participants over a 29-year follow-up period.
They found that participants with the highest levels of vitamin D (more than 50 nmol/L) had a 65
percent lower risk of developing Parkinson's disease than those with the lowest vitamin D levels (less
than 25 nmol/L). The researchers accounted for potentially confounding variables such as age, sex,
marital status, education, alcohol consumption, smoking, physical activity and month of blood draw.
The results of the study of Paul Knekt, et al, [34] are consistent with the suggestion that high vitamin
D status provides protection against Parkinson disease. The authors suggested that The vitamin D
receptors and an enzyme responsible for the formation of the active form 1,25-hydroxyvitamin D
have been found in high levels in the substantia nigra, the region of the brain affected most by
Parkinson disease. This raises the possibility that chronic inadequacy of vitamin D leads to the loss
of dopaminergic neurons in the substantia nigra region and further Parkinson disease.
Vitamin D is also believed to protect the brain through antioxidant activity, regulating calcium levels,
detoxification, and its effect on the immune system and nerves.

4. o Vitamin E
A high intake of dietary vitamin E may protect against the occurrence of PD. [35] Vitamin E is
believed to lower the risk for Parkinson disease through its antioxidant activity.
o Vitamin C
The investigators found that neither vitamin C nor carotenoid intake lowered the risk of developing
PD. [36,37] Also the studies of Mahyar at al, [36] did not suggest any protective effects associated
with vitamin C or β carotene. The results were the same for the use of vitamin E pills. Surprisingly,
participants who ate vitamin E–rich foods as part of their diets developed the fewest cases of PD.
 Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease
A Hawaiian study [27] published in the Journal of the American Medical Association (May 2000), has
shown that of 8,000 Japanese/American men, those who drank 3+ cups of coffee per day were 5
times less likely to develop Parkinson's disease. The study took place over a 30-year period. The
theory is that caffeine is reducing the amount of neuro-transmitters produced by the brain,
transmitters that may actually do damage to surrounding brain tissue. The actual action of caffeine
in the brain is not known. It may also interfere with uptake of other transmitters, allowing the levels
of dopamine to increase. The polyphenols in green tea may also have a preventative effect with
regards to Parkinson's disease. These chemicals act within the brain to improve the flow of
dopamine between portions of the brain. Parkinson's is caused by a lack of dopamine in one part of
the brain, and these polyphenols could prevent that depletion.
Webster Ross, et al, [27] findings indicate that higher coffee and caffeine intake is associated with a
significantly lower incidence of PD. This effect appears to be independent of smoking. The data
suggest that the mechanism is related to caffeine intake and not to other nutrients contained in
coffee.
Webster Ross, et al, [27] prospective study had demonstrated a significant inverse association
between coffee consumption measured during midlife and incident PD with a dose-response
relationship. The finding was consistent whether coffee intake was determined by 24-hour recall or
by food frequency questionnaire. The association was also observed for coffee intake measured at
different examinations 6 years apart.

5.  Cigarette smoking and the risk for Parkinson disease
Research on cigarette smoking and PD is one area that has been widely researched and yields
consistent findings across studies. Overall, cigarette smoking appears to be a protective factor
against developing PD. Gorell et al [7] showed that smoking more than 30 packs per year was
associated with a decreased chance of developing PD (OR 0.42, 95% CI, 0.25–0.71). In monozygotic
and dizygotic twin pairs in which at least one twin had PD, the risk of developing PD was inversely
related to the amount of cigarette smoking [12]. In an animal model of PD initiated by MPTP
intoxication, exposure to cigarette smoke led to a decrease in the loss of dopaminergic neurons in
substantia nigra. Taken together, such results suggest that frequent nicotine exposure may have a
neuroprotective effect on the dopaminergic nigrostriatal system [10].
Although the mechanism by which nicotine produces its effect is not known, several have been
hypothesized. One mechanism that has been proposed is through the ability of nicotine to block the
effects of two endogenous or exogenous dopaminergic proneurotoxicants, 1,2,3,4-
tetrahydroisoquinoline and 1,2,3,4-tetrahydro-ß-carboline [1,9]. Alternatively, nicotine may also act
by stimulating a neurotrophic factor, fibroblast growth factor-2, which is believed to protect the
dopamine-containing cells in the substantia nigra [1,8]. DiMonte et al [12] reviews the mechanisms
behind the association between smoking and neuroprotection with regard to PD. Two possible
mechanisms they propose are that nicotine may be neuroprotective in itself or nicotine may inhibit
monoamine oxidase activity and dopamine turnover, thereby preventing nigrostriatal damage.
 Rural residency and the risk for Parkinson disease
A rural residency appears to increase the risk of the development of PD and in particular young-
onset PD. [21,22,23] However, this finding has not been confirmed in all studies. [22,23,24] In
addition, a further lifestyle study showed increased herbicide exposure in patients with PD. [22]
Some studies have found that the significant association of PD with farming as an occupation cannot
be accounted for by pesticide exposure alone. [22] Another rural factor that has been linked to PD is
the consumption of well water,[25] although this may simply be further evidence in support of
herbicides or pesticides as etiological factors for PD.
 Type 2 diabetes and the risk for Parkinson disease
Although the association between parkinsonian manifestations (vascular parkinsonism) and
microvascular brain disease can be attributed to the pathologic findings of multiple basal ganglia
cavitations (etat crible) and infarcts (etat lacunaris) that are encountered in the ischemic

6. microvascular brain disease, however a link between the idiopathic parkinson disease and type 2
diabetes was demonstrated by Hu, et al, [26]. Hu, G, et al, [26] found that individuals who developed
type 2 diabetes have an 83% increased risk for PD compared with the general population. The
mechanism of the association between type 2 diabetes and PD is, however, poorly understood.
Insulin might play a role in the regulation of central dopaminergic transmission. [26] According to
the study of Hu, et al, [26] The association between type 2 diabetes and PD is independent of sex,
smoking, alcohol and coffee intake, and body weight. The demonstrated link between the idiopathic
parkinson disease and type 2 diabetes could result in increased incidence of the idiopathic parkinson
disease in the microvascular brain disease that is independent of any structural ischemic cerebral
pathology.
 The metabolic syndrome and the risk for Parkinson disease
Dopamine is involved in the regulation of food intake, and obese persons have decreased dopamine
D2 receptor availability in the striatum. Furthermore, midlife triceps skinfold thickness has been
found to be positively associated with the risk of Parkinson's disease (PD) among Japanese-American
men in Hawaii.
Obesity is a well-known risk factor for coronary heart disease and type II diabetes. type II diabetes
itself is associated with increased risk for Idiopathic Parkinson disease [26]. Previous investigations
have suggested that abdominal obesity, as measured by waist circumference or waist-to-hip ratio,
increases the risk of these diseases independently of overall obesity. Honglei Chen et al, suggested
that abdominal obesity may increase Parkinson’s disease risk among nonsmokers. [32]
 Other risk factors for Parkinson disease
o Age
The average age of onset of Parkinson's disease is 55. About 10% of Parkinson's cases are in people
younger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinson's
disease.
o Gender
Parkinson ' s disease is more common in men than in women.

7. o Family History
People with siblings or parents who developed Parkinson's at a younger age are at higher risk for
Parkinson's disease, but relatives of those who were elderly when they had the disease appear to
have an average risk.
o Race and Ethnicity
African- and Asian-Americans appear to have a lower risk than Caucasians.

8. Factors that increase risk for idiopathic parkinson disease
Type 2 diabetes and the risk for A link between the idiopathic parkinson disease and type
Parkinson disease 2 diabetes was demonstrated by Hu, et al, [26].
Initiation of any antidepressant This suggests that depressive symptoms could be an early
therapy was associated with a manifestation of PD, preceding motor dysfunction. [31]
higher risk of PD in the 2 years
after the start of treatment
Significant head injury with Closed head injury with Repeated concussions increase
repeated concussion increase risk for Parkinson disease
the risk for PD in later
life.[18,19]
A rural residency A rural residency appears to increase the risk of the
development of PD and in particular young-onset PD.
[21,22,23]
Exposure to solvents [29] and Exposure to solvents [29] and heavy metals Increase risk
heavy metals. for PD
Age Aging increase risk for Parkinson disease
Gender Parkinson ' s disease is more common in men than in
women.
Race and Ethnicity African- and Asian-Americans appear to have a lower risk
than Caucasians.
The metabolic syndrome Honglei Chen et al, suggested that abdominal obesity may
increase Parkinson’s disease risk among nonsmokers. [32]

9. Factors that reduce risk for idiopathic parkinson disease
Cigarette smoking Overall, cigarette smoking appears to be a protective factor
against developing PD.
Association of Coffee and Overall, Coffee intake appears to be a protective factor
Caffeine Intake against developing PD. Higher coffee and caffeine intake is
associated with a significantly lower incidence of PD.
Nonsteroidal anti-inflammatory Anti-inflammatory drugs may prevent Parkinson disease
drug (PD) by inhibiting a putative underlying neuroinflammatory
process.
High uric acid levels High uric acid levels may be associated with a reduced risk
for PD.[17]
Serum Vitamin D Vitamin D may protect against Parkinson's even though the
mechanism is not understood, although there is limited
evidence from cell-based and animal models that vitamin D
may prevent the loss of dopaminergic neurons. High serum
levels of vitamin D is associated with reduced risk for
parkinson disease.
Vitamin E A high intake of dietary vitamin E may protect against the
occurrence of PD.
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