Risk factors for idiopathic Parkinson diseaseThe author: Professor Yasser Metwallyhttp://yassermetwally.comINDEX 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
INTRODUCTIONDecember 7, 2011 — Two environmental factors are recognized to lower the risk for PD, cigarettesmoking  and coffee drinking.  The mechanisms through which they can reduce risk are notknown. Coffee drinking appears more protective for men, and so it is possible that there may be aninteraction 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. Animal andepidemiologic studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease theincidence of Parkinson disease (PD).Initiation of any antidepressant therapy was associated with a higher risk of PD in the 2 years afterthe start of treatment, which suggests that depressive symptoms could be an early manifestation ofPD, preceding motor dysfunction. High uric acid levels may be associated with a reduced risk for PD. Significant head injuryincreases the risk for PD in later life.[18,19] The effects of physical activity, estrogen status (despitethe 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 environmentalexposures that have variably been associated with a modest increased risk for PD, but theirrelevance to the majority of PD patients remains uncertain. These include exposure to solvents and heavy metals, which may, for instance, in the case of copper cause mitochondrial dysfunctionand Wilsons disease,  an important differential diagnosis of PD. Anti-inflammatory drugs and the Risk of Parkinson DiseaseAnti-inflammatory drugs may prevent Parkinson disease (PD) by inhibiting a putative underlyingneuroinflammatory process. Animal and epidemiologic studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of Parkinson disease (PD). Miguel, et al, 2006 studied 1,258 PD cases and 6,638 controls from the General Practice Research Database. Theodds ratios (95% CI) for ever vs never use were 0.93 (0.80 to 1.08) for nonaspirin NSAIDs, 1.29 (1.05to 1.58) for aspirin, and 1.16 (1.00 to 1.35) for acetaminophen. Nonaspirin NSAID use wasassociated with a higher risk in women and a lower risk in men.
Uric acid and the risk for Parkinson diseaseOxidative stress contributes to dopaminergic neuron degeneration in Parkinsons disease. Urate, apotent antioxidant, could be neuroprotective. MG Weisskopf et al.  suggested that high plasmaurate concentrations may decrease the risk of Parkinsons disease, and they raised the possibilitythat interventions to increase plasma urate may reduce the risk and delay the progression ofParkinsons disease. Vitamin D and Vitamin E and Vitamin C and the risk for Parkinson disease o Vitamin DVitamin D may protect against Parkinsons even though the mechanism is not understood, althoughthere is limited evidence from cell-based and animal models that vitamin D may prevent the loss ofdopaminergic neurons. High serum levels of vitamin D is associated with reduced risk for parkinsondisease. Individuals with higher serum vitamin D concentrations showed a reduced risk of Parkinsondisease. The sudy led by Paul Knekt and colleagues  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 79determined to be free of Parkinsons disease at the start of the study. The researchers thenexamined the incidence of Parkinsons 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 65percent lower risk of developing Parkinsons disease than those with the lowest vitamin D levels (lessthan 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,  are consistent with the suggestion that high vitaminD status provides protection against Parkinson disease. The authors suggested that The vitamin Dreceptors and an enzyme responsible for the formation of the active form 1,25-hydroxyvitamin Dhave been found in high levels in the substantia nigra, the region of the brain affected most byParkinson disease. This raises the possibility that chronic inadequacy of vitamin D leads to the lossof 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.
o Vitamin EA high intake of dietary vitamin E may protect against the occurrence of PD.  Vitamin E isbelieved to lower the risk for Parkinson disease through its antioxidant activity. o Vitamin CThe investigators found that neither vitamin C nor carotenoid intake lowered the risk of developingPD. [36,37] Also the studies of Mahyar at al,  did not suggest any protective effects associatedwith 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 DiseaseA Hawaiian study  published in the Journal of the American Medical Association (May 2000), hasshown that of 8,000 Japanese/American men, those who drank 3+ cups of coffee per day were 5times less likely to develop Parkinsons disease. The study took place over a 30-year period. Thetheory 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 caffeinein the brain is not known. It may also interfere with uptake of other transmitters, allowing the levelsof dopamine to increase. The polyphenols in green tea may also have a preventative effect withregards to Parkinsons disease. These chemicals act within the brain to improve the flow ofdopamine between portions of the brain. Parkinsons is caused by a lack of dopamine in one part ofthe brain, and these polyphenols could prevent that depletion.Webster Ross, et al,  findings indicate that higher coffee and caffeine intake is associated with asignificantly lower incidence of PD. This effect appears to be independent of smoking. The datasuggest that the mechanism is related to caffeine intake and not to other nutrients contained incoffee.Webster Ross, et al,  prospective study had demonstrated a significant inverse associationbetween coffee consumption measured during midlife and incident PD with a dose-responserelationship. The finding was consistent whether coffee intake was determined by 24-hour recall orby food frequency questionnaire. The association was also observed for coffee intake measured atdifferent examinations 6 years apart.
Cigarette smoking and the risk for Parkinson diseaseResearch on cigarette smoking and PD is one area that has been widely researched and yieldsconsistent findings across studies. Overall, cigarette smoking appears to be a protective factoragainst developing PD. Gorell et al  showed that smoking more than 30 packs per year wasassociated with a decreased chance of developing PD (OR 0.42, 95% CI, 0.25–0.71). In monozygoticand dizygotic twin pairs in which at least one twin had PD, the risk of developing PD was inverselyrelated to the amount of cigarette smoking . In an animal model of PD initiated by MPTPintoxication, exposure to cigarette smoke led to a decrease in the loss of dopaminergic neurons insubstantia nigra. Taken together, such results suggest that frequent nicotine exposure may have aneuroprotective effect on the dopaminergic nigrostriatal system .Although the mechanism by which nicotine produces its effect is not known, several have beenhypothesized. One mechanism that has been proposed is through the ability of nicotine to block theeffects 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 actby stimulating a neurotrophic factor, fibroblast growth factor-2, which is believed to protect thedopamine-containing cells in the substantia nigra [1,8]. DiMonte et al  reviews the mechanismsbehind the association between smoking and neuroprotection with regard to PD. Two possiblemechanisms they propose are that nicotine may be neuroprotective in itself or nicotine may inhibitmonoamine oxidase activity and dopamine turnover, thereby preventing nigrostriatal damage. Rural residency and the risk for Parkinson diseaseA 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] Inaddition, a further lifestyle study showed increased herbicide exposure in patients with PD. Some studies have found that the significant association of PD with farming as an occupation cannotbe accounted for by pesticide exposure alone.  Another rural factor that has been linked to PD isthe consumption of well water, although this may simply be further evidence in support ofherbicides or pesticides as etiological factors for PD. Type 2 diabetes and the risk for Parkinson diseaseAlthough the association between parkinsonian manifestations (vascular parkinsonism) andmicrovascular brain disease can be attributed to the pathologic findings of multiple basal gangliacavitations (etat crible) and infarcts (etat lacunaris) that are encountered in the ischemic
microvascular brain disease, however a link between the idiopathic parkinson disease and type 2diabetes was demonstrated by Hu, et al, . Hu, G, et al,  found that individuals who developedtype 2 diabetes have an 83% increased risk for PD compared with the general population. Themechanism 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.  According tothe study of Hu, et al,  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 idiopathicparkinson disease and type 2 diabetes could result in increased incidence of the idiopathic parkinsondisease in the microvascular brain disease that is independent of any structural ischemic cerebralpathology. The metabolic syndrome and the risk for Parkinson diseaseDopamine is involved in the regulation of food intake, and obese persons have decreased dopamineD2 receptor availability in the striatum. Furthermore, midlife triceps skinfold thickness has beenfound to be positively associated with the risk of Parkinsons disease (PD) among Japanese-Americanmen in Hawaii.Obesity is a well-known risk factor for coronary heart disease and type II diabetes. type II diabetesitself is associated with increased risk for Idiopathic Parkinson disease . Previous investigationshave 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, suggestedthat abdominal obesity may increase Parkinson’s disease risk among nonsmokers.  Other risk factors for Parkinson disease o AgeThe average age of onset of Parkinsons disease is 55. About 10% of Parkinsons cases are in peopleyounger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinsonsdisease. o GenderParkinson s disease is more common in men than in women.
o Family HistoryPeople with siblings or parents who developed Parkinsons at a younger age are at higher risk forParkinsons disease, but relatives of those who were elderly when they had the disease appear tohave an average risk. o Race and EthnicityAfrican- and Asian-Americans appear to have a lower risk than Caucasians.
Factors that increase risk for idiopathic parkinson diseaseType 2 diabetes and the risk for A link between the idiopathic parkinson disease and typeParkinson disease 2 diabetes was demonstrated by Hu, et al, .Initiation of any antidepressant This suggests that depressive symptoms could be an earlytherapy was associated with a manifestation of PD, preceding motor dysfunction. higher risk of PD in the 2 yearsafter the start of treatmentSignificant head injury with Closed head injury with Repeated concussions increaserepeated concussion increase risk for Parkinson diseasethe risk for PD in laterlife.[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  and Exposure to solvents  and heavy metals Increase riskheavy metals. for PDAge Aging increase risk for Parkinson diseaseGender 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. 
Factors that reduce risk for idiopathic parkinson diseaseCigarette 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 factorCaffeine 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 diseasedrug (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.Serum Vitamin D Vitamin D may protect against Parkinsons 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.References 1. Mayeaux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81–104. 2. DEpiro P. Keeping current in Alzheimers disease. Patient Care. 1999;13:127–139. 3. Richards SS, Hendrie HC. Diagnosis, management and treatment of Alzheimers disease: a guide for the internist. Arch Intern Med. 1999;159:789–801. 4. Morris JC. Differential diagnosis of Alzheimers disease. Clin Geriatr Med. 1994;10:257–276. 5. Jorm AF, Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998;51:728–733. 6. Gao S, Hendrie HC, Hall KS, et al.. The relationship between age, sex, and the incidence of dementia and Alzheimers disease: a meta-analysis. Arch Gen Psychiatry. 1998;55:809–815. 7. Gorell J, Peterson E, Rybicki B, et al.. Multiple risk factors for Parkinsons disease. J Neurol Sci. 2004;217(2):169–174. 8. Tanner C, Goldman S, Aston D, et al.. Smoking and Parknsons disease in twins. Neurology. 2002;58:581–588. 9. Maggio R, Riva M, Vaglini F, et al.. Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors. J Neurochem. 1998;71(6):2439–2446.
10. Soto-Otero R, Mendez-Alvarez E, Sanchez-Sellero I, et al.. Reduction of rat brain levels of the endogenous dopaminergic proneurotoxinx 1,2,3,4-tetrehydroisoquinoline and 1,2,3,4- tetrahydro-bet-carboline by cigarette smoke. Neurosci Lett. 2001;298(3):187–190.11. Parain K, Hapdey C, Rousselet E, et al.. Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonian toxin. Brain Res. 2003;984:224–232.12. DiMonte D, Lavasani M, Manning-Bog A. Environmental factors in Parkinsons disease. Neurotoxicology. 2002;23:487–502.13. Tanner C, Goldman S, Aston D, et al.. Smoking and Parknsons disease in twins. Neurology. 2002;58:581–588.14. Baron JA. Cigarette smoking and Parkinsons disease. Neurology. 1986;36(11):1490–1496.15. Ascherio A, Zhang SM, Hernan MA, et al. Prospective study of caffeine consumption and risk of Parkinsons disease in men and women. Ann Neurol. 2001;50(1):56–63.16. Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol. 2003;60(8):1059–1064.17. Weisskopf MG, OReilly E, Chen H, et al. Plasma urate and risk of Parkinsons disease. Am J Epidemiol. 2007;166(5):561–567.18. Goldman SM, Tanner CM, Oakes D, et al. Head injury and Parkinsons disease risk in twins. Ann Neurol. 2006;60(1):65–72.19. Bower JH, Maraganore DM, Peterson BJ, et al. Head trauma preceding PD: a case-control study. Neurology. 2003;60(10):1610–1615.20. Gu M, Cooper JM, Butler P, et al. Oxidative-phosphorylation defects in liver of patients with Wilsons disease. Lancet. 2000;356(9228):469–474. Rajput AH, Uitti RJ, Stern W, et al. Early onset Parkinsons disease in Saskatchewan— environmental considerations for etiology. Can J Neurol Sci. 1986;13(4):312–316.21. Rajput AH, Uitti RJ, Rajput AH. Neurological disorders and services in Saskatchewan—a report based on provincial health care records. Neuroepidemiology. 1988;7(3):145–151.22. Behari M, Srivastava AK, Das RR, et al. Risk factors of Parkinsons disease in Indian patients. J Neurol Sci. 2001;190(1–2):49–55.23. Semchuk KM, Love EJ, Lee RG. Parkinsons disease and exposure to rural environmental factors: a population based case-control study. Can J Neurol Sci. 1991;18(3):279–286.
24. Barbeau A, Roy M, Bernier G, et al. Ecogenetics of Parkinsons disease: prevalence and environmental aspects in rural areas. Can J Neurol Sci. 1987;14(1):36–41.25. Gorrell JM, DiMonte D, Graham D. The role of the environment in Parkinsons disease. Environ Health Perspect. 1996;104(6):652–654.26. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J. Type 2 Diabetes and the Risk of Parkinsons Disease Diabetes Care 30:842-847, 2007 [Full text]27. Webster Ross, et all. Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease. Jama,2000;283(20):2674-2679. [Full text]28. Head trauma: Dementia pugilistica (chronic traumatic encephalopathy (CTE) [Full text]29. Solvents and parkinson disease [Full text]30. Miguel, et al,: Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease. Neurology April 11, 2006 vol. 66 no. 7 1097-1099 –[Abstract]31. Alonso,et al: Use of antidepressants and the risk of Parkinson’s disease: a prospective study. J Neurol Neurosurg Psychiatry2009;80:671-674 [Abstract]32. Honglei Chen et al,: Obesity and the Risk of Parkinson’s Disease. Am. J. Epidemiol. (2004) 159 (6): 547-555. [Full text]33. MG Weisskopf et al.: Plasma Urate and Risk of Parkinsons Disease. Am. J. Epidemiol. (2007) 166 (5): 561-567. [Full text]34. Paul Knekt et al,: Serum Vitamin D and the Risk of Parkinson Disease. Arch Neurol. 2010;67(7):808-811. [Full text]35. Maarten C et al: Dietary Antioxidants and Parkinson Disease. Arch Neurol. 1997;54(6):762-765. [Abstract]36. Mahyar et al: Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinsons disease: a meta-analysis. The lancet neurology.Volume 4, Issue 6, June 2005, Pages 362-365 [Abstract]37. Ghani, H et al: Vitamins and the Risk for Parkinson’s Disease. Neurology October 22, 2002 vol. 59 no. 8 E8-E9 [Abstract]