Movement Disorders Vol. 6 , NO. 2, 1991, pp. 95-97 0 1991 Movement Disorder Society
Viewpoint
Head Trauma As A Risk Factor For Parkinson’s Disease Matthew B. Stern Department of Neurology, Graduate Hospital and the University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, U.S.A.
claimed that trauma was related to PD in 15% of their patient sample studied in 1922. However, in a 1934 review of “Paralysis Agitans and Trauma,” Grimberg (6) considered only 2 of 86 cases to be true posttraumatic parkinsonism. Both patients sustained severe head injury that, according to Grimberg, was a necessary prerequisite for the diagnosis of posttraumatic PD. Similarly, Lindenberg (7) noted the onset of parkinsonism in three patients following severe head injury, although additional neurologic signs transcended the boundaries of the extrapyramidal system. These patients also had hemorrhagic lesions in the midbrain. Schwab and England (8) later confirmed that head trauma could cause parkinsonism only when severe enough to cause brainstem hemorrhage. Taken together, these observations suggest that parkinsonism can directly result from head trauma only when the injury is severe. In these cases, there is usually structural damage to the midbrain and additional neurologic manifestations including cerebellar and pyramidal tract signs as well as cognitive impairment. None of the patients reported in these studies would likely be confused with classic PD today. However, variable degrees of head trauma occurring years prior to clinical parkinsonism must be distinguished epidemiologically from the acute trauma and the sequelae covered in the aforementioned studies. More recently, epidemiological studies have focused on demographic factors and life experiences occurring years prior to the onset of PD when the underlying process causing PD begins. Head trauma has been positively linked to subsequent PD in several such studies. Godwin-Austen and colleagues (9) noted the association between head trauma and PD in their study of PD in England. In a study of PD in twins, Ward et al. (10) found that the twin affected with PD was more likely to have sustained an episode of minor head trauma than the unaffected twin. Factor and co-workers (1 1) found
In his essay on “The Shaking Palsy” in 1817, James Parkinson (1) suggested that symptoms of the disease that bears his name might result from injury to the superior portion of the cervical spine. While many of Parkinson’s original clinical observations have withstood the test of time, the concept of trauma-induced Parkinson’s disease (PD) has been largely refuted. Factor and colleagues (2) conclude in their comprehensive review of trauma and parkinsonism that “there is no evidence supporting the hypothesis that peripheral trauma or mild head trauma cause Parkinson’s disease.” They base their conclusions on the lack of any direct association between an episode of head trauma and pathologically proven PD, notwithstanding the well recognized akinetic-rigid syndromes that can occur as a consequence of severe head injury with prolonged loss of consciousness and other neurologic sequelae. However, the cascade of metabolic and pathologic changes eventually leading to PD begins many years prior to the onset of clinical manifestations (3,4), which become apparent once the critical threshold of dopamine loss has been exceeded. The crucial issue, then, is not whether head trauma can cause immediate clinical and pathologic PD, but whether or not head trauma can contribute to the underlying process that initiates dopamine neuronal degeneration. It is the task of epidemiology to ascertain the significance of head trauma in PD patients, while scientific models are designed to study its long-term neurochemical and pathologic effects.
THE EPIDEMIOLOGY OF HEAD TRAUMA IN PD
Head trauma has been linked to PD in numerous epidemiological surveys. Patrick and Levy ( 5 ) Address correspondence and reprint requests to Dr. M. B. Stem at Graduate Hospital, Suite 900, One Graduate Plaza, Philadelphia, PA 19146, U.S.A.
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M . B . STERN
that head trauma sufficient to cause transient loss of consciousness occurred 20-30 years prior to disease onset significantly more often in PD patients than in controls. In the author’s case-control study of young-onset (60 years of age) PD patients and matched controls, PD patients in both age groups were more likely than controls to have sustained head trauma severe enough to cause “vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes or paralysis” prior to the onset of PD (12). The authors of these studies were all appropriately cautious in their conclusions and questioned the true significance of head trauma in PD. Recall bias was cited as a possible explanation for the observed differences in head trauma prevalence between PD patients and unaffected controls. Patients with a chronic disease are more likely than healthy individuals to remember relatively trivial injuries in their quest to explain their symptoms. In Factor’s study (1 l), however, patients were considered to have a history of significant head trauma only when associated with loss of consciousness. Even healthy individuals are likely to remember such an episode. Similarly, the author’s survey asked patients and controls only to report head trauma sufficient to cause transient neurologic sequelae (12). Furthermore, young-onset patients in this study were, on average, 30 years younger than old-onset patients at the time of diagnosis, yet there was no difference in the prevalence of head trauma prior to disease onset between the two patient groups. If a relatively trivial medical event is easily remembered by patients with chronic diseases like PD, one might have expected that old-onset PD patients, with 30 years more of life experience, would have reported more episodes of head trauma than young-onset patients. It seems unlikely, therefore, that recall bias alone is responsible for the reported difference in prevalence of head trauma between patients and controls. Consequently, we are left with epidemiological observations that require further exploration. BOXER’S ENCEPHALOPATHY AND ALZHEIMER’S DISEASE Understanding the long-term effects of head trauma begins with an analysis of the pathology of brain injury. Concussive head trauma, for.example, causes diffuse axonal injury (axonal retraction balls, torn nerve fibers) that correlates with the duration of unconsciousness and severity of clinical
Movement Disorders, Vol. 6 , N o . 2, 1991
outcome (13). These changes occur as a consequence of acceleratioddeceleration forces and do not require skull fractures, contusions, or even superficial lacerations. Head trauma with only brief, minor neurologic sequelae might cause lesser degrees of axonal damage (14) and contribute to the brain’s vulnerability to other stresses such as aging. The concept of accumulating neurologic impairment related to head trauma is best exemplified by considering the syndrome of boxer’s encephalopathy or dementia pugilistica (DP), which causes neurologic symptoms long after the traumatic event(s). Martland (15) first described the “punch-drunk” syndrome with parkinsonian features in 1928. Parkinsonian features of DP include gait disequilibrium, cogwheel rigidity, bradykinesia, and even a resting tremor. As in Lewy-body PD, symptoms can evolve slowly, years after a boxer’s career has ended. Other neurologic manifestations of DP include dementia, cerebellar dysfunction, and pyramidal tract signs. The frequency of DP correlates with the number of professional bouts (and presumably the number and severity of blows to the head), and neurologic sequelae are now a well-recognized risk of professional boxing (16,17). Corsellis et al. (18) described the neuropathology of this syndrome. In addition to petechial hemorrhages in the cortex and brainstem and gliosis of the cerebellum, there is striking loss of pigmented neurons in the substantia nigra as in Lewy-body PD. However, Lewy bodies are not seen. Numerous neurofibrillary tangles (NFTs) without senile plaques (SPs) are present in the cerebral cortex. While gliosis and changes in the septum pellucidum can be explained by the cumulative effects of repeated head trauma, the occurrence of NFTs without SPs is puzzling and beckons the question of whether or not head trauma can indeed cause pathologic alterations that resemble other neurodegenerative diseases like Alzheimer’s disease (AD). In addition to PD, head trauma has been linked in epidemiological surveys to a number of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) (19,20) and AD (21,22). Recently, Roberts and co-workers (23) used immunocytochemical methods to re-examine the cases of DP studied originally by Corsellis and found extensive p-protein immunoreactive protein (the amyloid component of SPs) in all patients in whom standard staining techniques showed NFTs but no SPs. Standard staining techniques fail to reveal SPs. These data suggest that the pathologic changes of DP more closely resemble AD than has
HEAD TRAUMA AND PD
been previously considered and that SPs may be the final common pathway in both disorders. The pathologic mechanisms involved in NFT and SP formation might therefore be similar in AD and DP, despite different antecedent events and risk factors. Boxers sustain repeated head trauma; patients with AD may have several risk factors including age, genetic predisposition, and perhaps even head trauma. CONCLUSIONS The pathologic link between DP and AD suggests that head trauma may have more complex effects on the brain than has heretofore been appreciated. Head trauma might alter the blood-brain barrier, thus exposing the brain to substances (i.e., toxins and antigens) that precipitate or potentiate an evolving pathologic process. If head trauma can be pathologically linked to AD, we must view the repeated association between head trauma and PD with more scrutiny. A significant proportion of patients with PD develops a dementia that is clinically and pathologically similar to AD (24), suggesting a potential pathophysiologic link between PD and AD. Moreover, current evidence suggests that there is no single cause of PD; rather, a complex interaction between age, environmental factors, and perhaps even genetic predisposition is responsible (25,26). Head trauma might be one of several risk factors that are capable of combining in a predisposed individual to precipitate the chain of pathological events culminating in PD. Accumulating evidence suggests that the biochemical, immunological, and pathologic effects of head trauma be further studied to elucidate its possible relationship to PD and other neurodegenerative disorders. REFERENCES 1. Parkinson J. Essay on the shakingpalsy. London: Whittingham and Rowland, for Shenvood, Neely and Jones, 1817. 2. Factor S, Sanchez-Ramos J, Weiner WJ. Trauma as an etiology of parkinsonism: a historical review of the concept. Movement Disord 1988;3:30-7. 3. Scherman D, Desnos C, Darchen F, et al. Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann Neurol 1989;26:551-7. 4. Riederer P, Wuketich S. Time course of nigrostriatal degeneration in Parkinson’s disease. J Neurol Transm 1976; 38:277-301.
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5. Patrick HU, Levy PM. Parkinson’s disease. A clinical study of one hundred and forty-six cases. Arch Neurol Psychiatry 1922;7:711-20. 6. Grimberg L. Paralysis agitans and trauma. J Nerv Ment Dis 1934;79:1442. 7. Lindenberg R. Die schadigungs mechanismen der substantia nigra bei himtraumen und das problem des poattravmatischen parkinsonismus. Dtsch Z Nervenheilkd 1964;185:63763. 8. Schwab RS, England AC. Parkinsonism due to various specific causes. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 6, 1st edition. Amsterdam: NorthHolland Publishing Co., 1968:230-3. 9. Godwin-Austen RB, Lee DN, Marmot MG, et al. Smoking and Parkinson’s disease. J Neurol Neurosurg Psychiatry 1982;44:577-81. 10. Ward CD, Duvoisin RC, Ince SE, et al. Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983;33:815-24. 11. Factor SA, Weiner WJ. Head trauma and Parkinson’s disease. Movement Disord 1990;5(suppl):13. 12. Stem M, Dulaney E, Gruber S, et al. Risk factors for Parkinson’s disease: a case-control study of young and old onset patients. Ann Neurol 1990;28:294. 13. Gennarelli TA, Thibault LE, Adam JH. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:56&74. 14. Jennett B. Head trauma. In: Asbury AK, McKhann GM, McDonald WI, eds. Diseases of the nervous system: clinical neurobiology. Philadelphia: W.B. Saunders, 1986: 1282-5. 15. Martland HS. Punch drunk. JAMA 1928;91:1103-7. 16. Roberts AJ. Brain damage in boxers. London: Pitman Medical Scientific Publications, 1969. 17. Stiller JW, Weinberger DR. Boxing and chronic brain damage. Psychiatr Clin North Am 1985;8:339-56. 18. Corsellis J, Bruton C, Freeman-Browne D. The aftermath of boxing. Psycho1 Med 1983;3:270-303. 19. Gallagher JP, Sanders M. Trauma and amyotrophic lateral sclerosis: a report of 78 patients. Acta Neurol Scand 1987;75:145-50. 20. Sienko DG, Davis JP, Taylor JA, Brooks BR. Amyotrophic lateral sclerosis: a case-control study following detection of a cluster in a small Wisconsin community. Arch Neurol 1990;47:38-41. 21. French LR, Schuman LM, Mortimer JA, et al. A casecontrol study of dementia of the Alzheimer type. Am J Epidemiol 1985 ;121 :414-2 1 . 22. Rudelli R, Strom JO, Welch PT, et al. Post-traumatic premature Alzheimer’s disease: neuropathologic findings and pathogenetic considerations. Arch Neurol 1982;39:570-5. 23. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53:3734. 24. Stem M, Gur R, Saykin A, Hurtig H. The dementia of Parkinson’s disease and Alzheimer’s disease: is there a difference? J Am Gerialr SOC 1986;34:475-8. 25. Calne DB. Current concepts on the etiology of Parkinson’s disease. Movement Disord 1989;4(suppl):5114. 26. Johnson WG, Hodge SE, Duvoisin R. Twin studies and the genetics of Parkinson’s disease-a reappraisal. Movement Disord 19905:187-94.
Movement Disorders, Vol. 6 , No. 2, 1991
Viewpoint
Head Trauma As A Risk Factor For Parkinson’s Disease Matthew B. Stern Department of Neurology, Graduate Hospital and the University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, U.S.A.
claimed that trauma was related to PD in 15% of their patient sample studied in 1922. However, in a 1934 review of “Paralysis Agitans and Trauma,” Grimberg (6) considered only 2 of 86 cases to be true posttraumatic parkinsonism. Both patients sustained severe head injury that, according to Grimberg, was a necessary prerequisite for the diagnosis of posttraumatic PD. Similarly, Lindenberg (7) noted the onset of parkinsonism in three patients following severe head injury, although additional neurologic signs transcended the boundaries of the extrapyramidal system. These patients also had hemorrhagic lesions in the midbrain. Schwab and England (8) later confirmed that head trauma could cause parkinsonism only when severe enough to cause brainstem hemorrhage. Taken together, these observations suggest that parkinsonism can directly result from head trauma only when the injury is severe. In these cases, there is usually structural damage to the midbrain and additional neurologic manifestations including cerebellar and pyramidal tract signs as well as cognitive impairment. None of the patients reported in these studies would likely be confused with classic PD today. However, variable degrees of head trauma occurring years prior to clinical parkinsonism must be distinguished epidemiologically from the acute trauma and the sequelae covered in the aforementioned studies. More recently, epidemiological studies have focused on demographic factors and life experiences occurring years prior to the onset of PD when the underlying process causing PD begins. Head trauma has been positively linked to subsequent PD in several such studies. Godwin-Austen and colleagues (9) noted the association between head trauma and PD in their study of PD in England. In a study of PD in twins, Ward et al. (10) found that the twin affected with PD was more likely to have sustained an episode of minor head trauma than the unaffected twin. Factor and co-workers (1 1) found
In his essay on “The Shaking Palsy” in 1817, James Parkinson (1) suggested that symptoms of the disease that bears his name might result from injury to the superior portion of the cervical spine. While many of Parkinson’s original clinical observations have withstood the test of time, the concept of trauma-induced Parkinson’s disease (PD) has been largely refuted. Factor and colleagues (2) conclude in their comprehensive review of trauma and parkinsonism that “there is no evidence supporting the hypothesis that peripheral trauma or mild head trauma cause Parkinson’s disease.” They base their conclusions on the lack of any direct association between an episode of head trauma and pathologically proven PD, notwithstanding the well recognized akinetic-rigid syndromes that can occur as a consequence of severe head injury with prolonged loss of consciousness and other neurologic sequelae. However, the cascade of metabolic and pathologic changes eventually leading to PD begins many years prior to the onset of clinical manifestations (3,4), which become apparent once the critical threshold of dopamine loss has been exceeded. The crucial issue, then, is not whether head trauma can cause immediate clinical and pathologic PD, but whether or not head trauma can contribute to the underlying process that initiates dopamine neuronal degeneration. It is the task of epidemiology to ascertain the significance of head trauma in PD patients, while scientific models are designed to study its long-term neurochemical and pathologic effects.
THE EPIDEMIOLOGY OF HEAD TRAUMA IN PD
Head trauma has been linked to PD in numerous epidemiological surveys. Patrick and Levy ( 5 ) Address correspondence and reprint requests to Dr. M. B. Stem at Graduate Hospital, Suite 900, One Graduate Plaza, Philadelphia, PA 19146, U.S.A.
95
96
M . B . STERN
that head trauma sufficient to cause transient loss of consciousness occurred 20-30 years prior to disease onset significantly more often in PD patients than in controls. In the author’s case-control study of young-onset (60 years of age) PD patients and matched controls, PD patients in both age groups were more likely than controls to have sustained head trauma severe enough to cause “vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes or paralysis” prior to the onset of PD (12). The authors of these studies were all appropriately cautious in their conclusions and questioned the true significance of head trauma in PD. Recall bias was cited as a possible explanation for the observed differences in head trauma prevalence between PD patients and unaffected controls. Patients with a chronic disease are more likely than healthy individuals to remember relatively trivial injuries in their quest to explain their symptoms. In Factor’s study (1 l), however, patients were considered to have a history of significant head trauma only when associated with loss of consciousness. Even healthy individuals are likely to remember such an episode. Similarly, the author’s survey asked patients and controls only to report head trauma sufficient to cause transient neurologic sequelae (12). Furthermore, young-onset patients in this study were, on average, 30 years younger than old-onset patients at the time of diagnosis, yet there was no difference in the prevalence of head trauma prior to disease onset between the two patient groups. If a relatively trivial medical event is easily remembered by patients with chronic diseases like PD, one might have expected that old-onset PD patients, with 30 years more of life experience, would have reported more episodes of head trauma than young-onset patients. It seems unlikely, therefore, that recall bias alone is responsible for the reported difference in prevalence of head trauma between patients and controls. Consequently, we are left with epidemiological observations that require further exploration. BOXER’S ENCEPHALOPATHY AND ALZHEIMER’S DISEASE Understanding the long-term effects of head trauma begins with an analysis of the pathology of brain injury. Concussive head trauma, for.example, causes diffuse axonal injury (axonal retraction balls, torn nerve fibers) that correlates with the duration of unconsciousness and severity of clinical
Movement Disorders, Vol. 6 , N o . 2, 1991
outcome (13). These changes occur as a consequence of acceleratioddeceleration forces and do not require skull fractures, contusions, or even superficial lacerations. Head trauma with only brief, minor neurologic sequelae might cause lesser degrees of axonal damage (14) and contribute to the brain’s vulnerability to other stresses such as aging. The concept of accumulating neurologic impairment related to head trauma is best exemplified by considering the syndrome of boxer’s encephalopathy or dementia pugilistica (DP), which causes neurologic symptoms long after the traumatic event(s). Martland (15) first described the “punch-drunk” syndrome with parkinsonian features in 1928. Parkinsonian features of DP include gait disequilibrium, cogwheel rigidity, bradykinesia, and even a resting tremor. As in Lewy-body PD, symptoms can evolve slowly, years after a boxer’s career has ended. Other neurologic manifestations of DP include dementia, cerebellar dysfunction, and pyramidal tract signs. The frequency of DP correlates with the number of professional bouts (and presumably the number and severity of blows to the head), and neurologic sequelae are now a well-recognized risk of professional boxing (16,17). Corsellis et al. (18) described the neuropathology of this syndrome. In addition to petechial hemorrhages in the cortex and brainstem and gliosis of the cerebellum, there is striking loss of pigmented neurons in the substantia nigra as in Lewy-body PD. However, Lewy bodies are not seen. Numerous neurofibrillary tangles (NFTs) without senile plaques (SPs) are present in the cerebral cortex. While gliosis and changes in the septum pellucidum can be explained by the cumulative effects of repeated head trauma, the occurrence of NFTs without SPs is puzzling and beckons the question of whether or not head trauma can indeed cause pathologic alterations that resemble other neurodegenerative diseases like Alzheimer’s disease (AD). In addition to PD, head trauma has been linked in epidemiological surveys to a number of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) (19,20) and AD (21,22). Recently, Roberts and co-workers (23) used immunocytochemical methods to re-examine the cases of DP studied originally by Corsellis and found extensive p-protein immunoreactive protein (the amyloid component of SPs) in all patients in whom standard staining techniques showed NFTs but no SPs. Standard staining techniques fail to reveal SPs. These data suggest that the pathologic changes of DP more closely resemble AD than has
HEAD TRAUMA AND PD
been previously considered and that SPs may be the final common pathway in both disorders. The pathologic mechanisms involved in NFT and SP formation might therefore be similar in AD and DP, despite different antecedent events and risk factors. Boxers sustain repeated head trauma; patients with AD may have several risk factors including age, genetic predisposition, and perhaps even head trauma. CONCLUSIONS The pathologic link between DP and AD suggests that head trauma may have more complex effects on the brain than has heretofore been appreciated. Head trauma might alter the blood-brain barrier, thus exposing the brain to substances (i.e., toxins and antigens) that precipitate or potentiate an evolving pathologic process. If head trauma can be pathologically linked to AD, we must view the repeated association between head trauma and PD with more scrutiny. A significant proportion of patients with PD develops a dementia that is clinically and pathologically similar to AD (24), suggesting a potential pathophysiologic link between PD and AD. Moreover, current evidence suggests that there is no single cause of PD; rather, a complex interaction between age, environmental factors, and perhaps even genetic predisposition is responsible (25,26). Head trauma might be one of several risk factors that are capable of combining in a predisposed individual to precipitate the chain of pathological events culminating in PD. Accumulating evidence suggests that the biochemical, immunological, and pathologic effects of head trauma be further studied to elucidate its possible relationship to PD and other neurodegenerative disorders. REFERENCES 1. Parkinson J. Essay on the shakingpalsy. London: Whittingham and Rowland, for Shenvood, Neely and Jones, 1817. 2. Factor S, Sanchez-Ramos J, Weiner WJ. Trauma as an etiology of parkinsonism: a historical review of the concept. Movement Disord 1988;3:30-7. 3. Scherman D, Desnos C, Darchen F, et al. Striatal dopamine deficiency in Parkinson’s disease: role of aging. Ann Neurol 1989;26:551-7. 4. Riederer P, Wuketich S. Time course of nigrostriatal degeneration in Parkinson’s disease. J Neurol Transm 1976; 38:277-301.
97
5. Patrick HU, Levy PM. Parkinson’s disease. A clinical study of one hundred and forty-six cases. Arch Neurol Psychiatry 1922;7:711-20. 6. Grimberg L. Paralysis agitans and trauma. J Nerv Ment Dis 1934;79:1442. 7. Lindenberg R. Die schadigungs mechanismen der substantia nigra bei himtraumen und das problem des poattravmatischen parkinsonismus. Dtsch Z Nervenheilkd 1964;185:63763. 8. Schwab RS, England AC. Parkinsonism due to various specific causes. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, Vol. 6, 1st edition. Amsterdam: NorthHolland Publishing Co., 1968:230-3. 9. Godwin-Austen RB, Lee DN, Marmot MG, et al. Smoking and Parkinson’s disease. J Neurol Neurosurg Psychiatry 1982;44:577-81. 10. Ward CD, Duvoisin RC, Ince SE, et al. Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983;33:815-24. 11. Factor SA, Weiner WJ. Head trauma and Parkinson’s disease. Movement Disord 1990;5(suppl):13. 12. Stem M, Dulaney E, Gruber S, et al. Risk factors for Parkinson’s disease: a case-control study of young and old onset patients. Ann Neurol 1990;28:294. 13. Gennarelli TA, Thibault LE, Adam JH. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:56&74. 14. Jennett B. Head trauma. In: Asbury AK, McKhann GM, McDonald WI, eds. Diseases of the nervous system: clinical neurobiology. Philadelphia: W.B. Saunders, 1986: 1282-5. 15. Martland HS. Punch drunk. JAMA 1928;91:1103-7. 16. Roberts AJ. Brain damage in boxers. London: Pitman Medical Scientific Publications, 1969. 17. Stiller JW, Weinberger DR. Boxing and chronic brain damage. Psychiatr Clin North Am 1985;8:339-56. 18. Corsellis J, Bruton C, Freeman-Browne D. The aftermath of boxing. Psycho1 Med 1983;3:270-303. 19. Gallagher JP, Sanders M. Trauma and amyotrophic lateral sclerosis: a report of 78 patients. Acta Neurol Scand 1987;75:145-50. 20. Sienko DG, Davis JP, Taylor JA, Brooks BR. Amyotrophic lateral sclerosis: a case-control study following detection of a cluster in a small Wisconsin community. Arch Neurol 1990;47:38-41. 21. French LR, Schuman LM, Mortimer JA, et al. A casecontrol study of dementia of the Alzheimer type. Am J Epidemiol 1985 ;121 :414-2 1 . 22. Rudelli R, Strom JO, Welch PT, et al. Post-traumatic premature Alzheimer’s disease: neuropathologic findings and pathogenetic considerations. Arch Neurol 1982;39:570-5. 23. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53:3734. 24. Stem M, Gur R, Saykin A, Hurtig H. The dementia of Parkinson’s disease and Alzheimer’s disease: is there a difference? J Am Gerialr SOC 1986;34:475-8. 25. Calne DB. Current concepts on the etiology of Parkinson’s disease. Movement Disord 1989;4(suppl):5114. 26. Johnson WG, Hodge SE, Duvoisin R. Twin studies and the genetics of Parkinson’s disease-a reappraisal. Movement Disord 19905:187-94.
Movement Disorders, Vol. 6 , No. 2, 1991
