Lewy Body Disease

Lewy Body Disease

TAMARA A. SMITH, MD, and RICHARD A. PRAYSON, MD, Cleveland, Ohio

ABSTRACT: Lewy bodies have historically been considered a histopathologic hallmark of idiopathic Parkinsonís disease. Recently, it has become clear that Lewy bodies play a role in neurodegenerative processes other than idiopathic Parkinsonís disease, including diffuse Lewy body disease and diffuse Lewy bodies with concomitant Alzheimerís disease changes. It is likely that these processes represent a spectrum of neurodegenerative change in which Lewy bodies play a pivotal role. Although much is known and has been written regarding the histopathology and pathophysiology of Lewy body diseases, specific criteria for their diagnosis remain problematic. Within the spectrum of Lewy body disease, overlap in clinical presentation and histopathologic findings has caused some to dismiss attempts at subcategorizing Lewy body disease as artificial. We present, in brief, current information and theories concerning the pathology and pathogenesis of Lewy body disease.

LEWY BODIES, first described in 1912 by F. H. Lewy,1 are distinctive neuronal inclusions that historically have been linked to idiopathic Parkinsonís disease and have been considered a diagnostic hallmark of this entity. In recent years, however, it has become clear that Lewy bodies may be seen in several different neurodegenerative processes that are clinically similar yet distinct from the prototype Lewy body disease, idiopathic Parkinsonís disease. Lewy bodies may be found in several other neurodegenerative processes and diseases (Table); with few exceptions, Lewy bodies are not essential for the diagnosis of most of these entities. The focus of this article is to examine and review the histopathologic findings as they pertain to three categories of disease in which Lewy bodies are diagnostically and clinically essential: (1) idiopathic Parkinsonís disease, (2) diffuse Lewy body disease, and (3) diffuse Lewy bodies with Alzheimerís disease changes.

WHAT IS A LEWY BODY?

Lewy bodies are eosinophilic structures located within the cytoplasm of neurons. Characteristically, although not consistently, they are circular and have a dense protein core surrounded by a peripheral halo (Fig 1). Lewy bodies may be single or multiple within a neuron and their size may vary. Lewy bodies may be seen in a variety of locations, and, depending on the anatomic location in which they are found, their appearance varies. Generally, they retain their characteristic appearance in brain stem locations (substantia nigra and locus ceruleus); however, in other locations such as the cerebral cortex, they are often much less eosinophilic, are more elongate, and usually lack a peripheral halo around the central core.

The ultrastructural appearance of the characteristic Lewy body has often been likened to a sunflower.2 It has a dense central core of circular-shaped structures with a rim of radiating filaments (7 to 20 nm in diameter), with the largest filaments being located at the periphery of the structure.2-4 A looser arrangement of filaments at the periphery corresponds to the halo often observed by light microscopy.5,6 In contrast, the ultrastructure of cortical Lewy bodies consists of a random arrangement of intermediate filaments without radial orientation or a distinct core.7 In addition, degenerate cell organelles have often been incorporated into the structure of the Lewy body.8

Generally, the Lewy body is thought to be the result of altered neurofilament metabolism and/or transport due to neuronal damage and subsequent degeneration, causing an accumulation of altered cytoskeletal elements.5 Immunohistochemically, Lewy bodies stain with a variety of antibodies. Most notable, however, is the invariable staining with antineurofilament and anti-ubiquitin antibodies. There are three types of neurofilament proteins, designated as H (high molecular weight), M (middle molecular weight), and L (low molecular weight). In brain stem Lewy bodies, epitopes from the entire length of H, M, and L neurofilaments are incorporated into the structure, but staining of the tail regions of types H and M is absent in the central core.9 In cortical Lewy bodies, an epitope in the tail region of neurofilament M stains virtually every Lewy body.10 In addition, these neurofilaments exist in both phosphorylated and nonphosphorylated states. In particular, Lewy bodies stain well with antibodies to phosphorylated neurofilaments.11 This suggests that the phosphorylated neurofilament proteins may be instrumental in the formation of Lewy bodies.

Anti-ubiquitin antibodies also stain both brain stem and cortical Lewy bodies.12 Ubiquitin plays a role in the breakdown of certain cytosolic protein and has been characterized as a ìheat-shock protein,î one induced during times of cell stress.

Pale bodies are spherical areas of eosinophilic material within the cytoplasm of the neuron that displace the melanin to the periphery. They lack a dense core and peripheral halo. While they are not diagnostic of Parkinsonís disease, most physicians would agree that their presence should induce a careful search for characteristic and diagnostic Lewy bodies. It is possible that they represent early immature Lewy bodies, since some have been shown to stain with the antibodies to phosphorylated neurofilaments and ubiquitin.13

Two structures that histologically may resemble and thus may be confused with Lewy bodies include the Marinesco body and the ìacidophilic pink granule.î The Marinesco body is also a circular eosinophilic inclusion that is generally much smaller in size than the Lewy body and is more typically located within the nucleus of neurons.14 The Marinesco body may occur within substantia nigra and locus ceruleus and its presence correlates with increasing age. It may also be seen in the setting of Parkinsonís disease. To date, its relationship to the Lewy body, if any, is not known. The acidophilic pink granule is a small eosinophilic cytoplasmic granule found in pigmented neurons, distributed among the neuromelanin granules.2 Its significance at this time is also unknown.

THE INCIDENTAL LEWY BODY

It is now recognized that about 5% to 10% of asymptomatic individuals have presumably insignificant numbers of Lewy bodies, usually located in substantia nigra.5 In 1990, Perry et al15 compared the presence of Lewy bodies in a group of patients screened to exclude any neurologic or psychiatric disorders with their presence in a group of patients in a neuropsychiatric ward of a geriatric hospital (excluding patients diagnosed with Alzheimerís disease). The former group had Lewy bodies in 2.3% of cases, while 9% of the latter group were found to have one or more Lewy bodies in brain stem locations. In all cases, the presence of Lewy bodies was associated with at least some degree of neuronal degeneration in substantia nigra. This information is in keeping with the current theory that this population of patients actually represents preclinical, idiopathic Parkinsonís disease and, if given enough time, will eventually develop characteristic parkinsonian symptoms.

IDIOPATHIC PARKINSONÍS DISEASE

Idiopathic Parkinsonís disease is a relentlessly progressive neurodegenerative disorder of unknown etiology that has an annual incidence rate of 7.7 to 17.9 cases per 100,000 population.16 Although first described in 1817 by James Parkinson,17 the exact etiology and factors that underlie this process of selective neuronal degeneration remain unclear. The onset of symptoms is usually between the ages of 50 and 70 years. The clinical diagnosis is dependent upon three main parameters: (1) clinical symptomatology including tremor, bradykinesia, and rigidity; (2) the exclusion of other entities that cause similar symptoms; and (3) documentation of response to appropriate therapy.

Pathology

At autopsy, external examination of the brain usually reveals no striking abnormality. The brain weight is typically normal for age.2,18 The most noticeable changes center around the pigmented nuclei in the brain stem. The substantia nigra in the mesencephalon is universally pale, due to loss of the pigmented dopaminergic neurons. The locus ceruleus in the pons is often similarly involved
(Fig 2).

The histologic correlation to the gross appearance includes selective neuronal degeneration with corresponding cell loss, most notably in substantia nigra and locus ceruleus (Fig 3). Neuron loss in substantia nigra preferentially involves the zona compacta. It is thought that at least 70% of neurons must be lost in substantia nigra before the patient becomes symptomatic.19 Pigment incontinence with melanin debris found lying free in the neurophil is a frequent concomitant finding and is due to cell death and release of intracytoplasmic contents, including neuromelanin. Neuromelanin debris may also be found within macrophages. In fact, depigmentation of substantia nigra is often not as visible grossly as one might expect because there still is melanin in the area, even if it is no longer in viable neurons. Gliosis, due to neuronal damage, is invariably present, as are Lewy bodies (Fig 4). Lewy body formation may also occur in many other locations, such as the nucleus basalis of Meynert, dorsal motor nucleus of the vagus nerve, innominate substance, amygdala and hippocampus region, spinal cord and sympathetic ganglia, and even the cerebral cortex.2,16,20-22 Lewy bodies in these secondary anatomic locations are often atypical in appearance, ie, less eosinophilic, more elongate, and lacking a peripheral halo.

Pathophysiology

Selective degeneration of the pigmented neurons in the substantia nigra of the mesencephalon results in a deficiency of the dopamine transmitter synthesized by these neurons.16 Dopamine normally carries excitatory impulses to the striatum (caudate and putamen) that subsequently travel through the globus pallidus. There are normally excitatory and inhibitory impulses exiting the globus pallidus. The inhibitory impulses use g-aminobutyric acid as their primary neurotransmitter, travel to the thalamus, and, in turn, transmit efferent impulses back to the cortex. This link between the cortex, striatum, palladium, and thalamus serves to modulate that phase of motor activity between the time that one consciously thinks about making a specific movement and the motor activity corresponding to the execution of that movement. Therefore, when there is a deficiency in dopamine (the excitatory nerve transmitter), as there is with idiopathic Parkinsonís disease, there is a relative predominance of the inhibitory output of the basal ganglia that is eventually transmitted back to the cortex. The end result can be thought of as a generalized slowing or inhibition of motor impulses producing symptoms of bradykinesia and rigidity.23

Etiology

The precise etiology of Parkinsonís disease continues to be elusive. Epidemiologic studies indicate that, as with Alzheimerís disease, Parkinsonís disease appears to be an age-related disorder.17,24 Studies examining the geographic variation of Parkinsonís disease have shown a higher incidence in Western populations as compared with Mediterranean and Asian populations.17 In addition, studies have shown a lower prevalence in black people than in white people, prompting some to suggest that cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from external toxins.17,25 Interestingly, cigarette smoking has been observed to have a negative correlation with the occurrence of Parkinsonís disease.17 It has been hypothesized that nicotine may somehow simulate endogenous dopamine or may serve a protective function against oxidative radicals.

Since the initial descriptions of MPTP (1-methyl,4-phenyl-1,2,3,6-tetrahydropyridine)ñ
induced parkinsonism, several studies have attempted to implicate environmental toxins in the pathogenesis of Parkinsonís disease. Documented cases of parkinsonism associated with exposure to manganese, mercury, carbon monoxide, carbon disulfide, and agricultural pesticides are anecdotal and do not explain the etiology in the vast majority of cases.17,26 MPTP is a meperidine analog that was accidentally discovered as a contaminant of illegally made drugs.26,27 The pathology in these cases is characterized by destruction of substantia nigra accompanied by a profound loss of dopamine and other neurotransmitters; however, Lewy bodies are not a prominent feature. As with Parkinsonís disease, symptoms are usually controlled by levodopa therapy. The MPTP by itself is not toxic; it is converted by monoamine oxidase B into a substance (MPP+) that binds to mitochondria in dopaminergic neurons, resulting in cell damage and death by a free radical mechanism.26,28,29

It is well known that monoamine oxidase B generates hydrogen peroxide during the breakdown of dopamine. With increasing age, endogenous protective mechanisms that guard against free radical damage are diminished. Sian et al30,31 showed reduced levels of glutathione, which serves as a protection against oxidative stress, within substantia nigra of patients with Parkinsonís disease. Increased lipid peroxidation, which may be a consequence of oxygen free-radical production, may also play a role in neuronal cell death. It also appears that neurons containing neuromelanin are intrinsically more susceptible to the effects of free radical damage. Studies have also shown increased iron in substantia nigra and in the Lewy bodies in Parkinsonís disease.32 Iron can bind neuromelanin, producing a complex suspected of inducing oxidative stress and lipid peroxidation.33

Recently, several reports have looked for abnormalities of the mitochondrial respiratory chain in Parkinsonís disease.34-37 These abnormalities, which were initially described in substantia nigra, have now been reported in striatum, skeletal muscle, and platelets.34 Specific enzyme assays have shown decreased complex I enzyme activity in the substantia nigra region in patients with Parkinsonís disease.34,36,37 Evidence of specific mitochondrial deoxyribonucleic acid (DNA) defects in patients with Parkinsonís disease is more tenuous. There certainly is an increased likelihood of small mutations within mitochondrial DNA after free radical injury. Whether such mutations play a role in making an individual more susceptible to Parkinsonís disease is not known.

Another possible etiologic factor that has been proposed to explain the cell death of neurons containing dopamine includes a reported loss of basic fibroblast growth factor, which has a trophic effect on mesencephalic dopaminergic neurons.38 Recently, an immunohistochemical study using a monoclonal anti-insulin receptor antibody showed an absence of staining in several areas of the brain, including substantia nigra in patients with Parkinsonís disease.39 Moroo and colleagues39 suggested that a dysfunction of the insulin receptor system may somehow play a role in the death of dopaminergic neurons.

The exact role of hereditary or genetic factors in the development of Parkinsonís disease remains a subject of much debate. A number of problems have plagued studies that have attempted to examine this issue, including lack of agreement regarding criteria of what constitutes Parkinsonís disease and the clinical heterogeneity of these patients, as well as incomplete examination of all family members. The first systematic genetic analysis of Parkinsonís disease was described by Mjönes in 1949.40 He described a family history positive for Parkinsonís disease in 79 of 194 patients (41%) and concluded that Par-
kinsonís disease was inherited as an autosomal dominant trait with a 60% penetrance.40 Several recent studies have also indicated a possible autosomal dominant inheritance pattern in a subset of patients with parkinsonism.41-44 Others have indicated a multifactorial pattern of inheritance in Parkinsonís disease.45,46 It has even been suggested that genetic anticipation and perhaps an unstable trinucleotide repeat may be involved.47 Studies of twins with Parkinsonís disease have been generally inconclusive due to the small numbers of patients included.48 Recently, Smith et al49 reported a higher risk of Parkinsonís disease in individuals with a metabolic defect in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene.

DIFFUSE LEWY BODY DISEASE

A key development in the delineation of Lewy body disorders has been the recent recognition that almost all patients with idiopathic Parkinsonís disease have a few Lewy bodies in their cerebral cortex.5 This previously has been largely unrecognized because cortical Lewy bodies, due to their atypical appearance, are difficult to detect on routine hematoxylin-eosin stains of histologic sections. Recently, it has been found that Lewy bodies are highlighted with anti-ubiquitin antibody and are thus more easily detected. When present, although found throughout the cortex, cortical and neocortical Lewy bodies are typically located in the neurons of cortical layers V and VI of the temporal lobe, the cingulate gyrus, and the insular cortex. Interestingly, Lewy bodies located outside the brain stem do not seem to be associated with the same degree of corresponding cell loss or gliosis.50 This discovery, along with an increased awareness that some patients previously thought to have idiopathic Parkinsonís disease had a prominent component of dementia, led to the separate designation of diffuse Lewy body disease.50-54 Estimates of the incidence of dementia in patients with Parkinsonís disease are as high as 81%, although the average is probably around 30%.55 No clear clinical criteria have yet been defined for this disorder. Diffuse Lewy body disease (DLBD) is thought to be a dementing syndrome somewhat akin to Alzheimerís disease, with subtle differences in clinical presentation. In fact, whether it is justified to classify DLBD as distinct from DLBD with Alzheimerís disease changes is still a matter of controversy. The onset of symptoms is at approximately 40 years of age, much earlier than with either Alzheimerís disease or idiopathic Parkinsonís disease. The clinical presentation of DLBD can vary widely. Dementia is a prominent feature, characterized by a fluctuating subacute/acute confusional state, and it is often associated with visual hallucinations and behavioral disturbances.5 Typical parkinsonian symptoms, particularly rigidity, usually develop sometime in the course of the disease.5,56 These patients may have dementia and not have extrapyramidal parkinsonian signs until late in the course of the disease.56

The histopathologic characteristics of DLBD are distinct. In addition to the typical brain stem pathology of idiopathic Parkinsonís disease, numerous widely distributed neocortical Lewy bodies are present (Fig 4).

The pathologic basis for dementia in Lewy body disease or idiopathic Parkinsonís disease is controversial. Kosaka et al57 suggested that, in diffuse Lewy body disease, the dementia was due primarily to the cortical Lewy body. In 75% of patients with typical, brain stem Lewy body disease (idiopathic Parkinsonís disease), dementia was thought to be due to degeneration of subcortical nuclei, especially the nucleus basalis of Meynert. In the other 25% of patients with brain stem Lewy body disease, the dementia was thought to be due to coexisting Alzheimerís disease changes.

DIFFUSE LEWY BODIES AND ALZHEIMERÍS DISEASE CHANGES

Pure diffuse Lewy body disease, as described, is actually rare. In reality, most cases with both brain stem and numerous neocortical and cortical Lewy bodies will also have some degree of concomitant Alzheimerís disease pathology.20,55,58-62 The onset of clinical symptoms is usually after the age of 60 years and is gradual, with a slow progression of dementia. The parkinsonian symptoms most commonly seen are bradykinesia and rigidity, and these usually develop late in the course of the disease. In addition, the survival time is shorter than for pure Alzheimerís disease. The histopathology is the same as that of DLBD, with the added feature of associated Alzheimerís-type pathology, including primarily neurofibrillary tangles and senile or neuritic plaques (Fig 4). Rarely, spongiform change in the neurophil has been described.63 The relative contribution to the clinical presentation of the different histopathologic changes remains unclear.

The pathogenic relationships between Lewy bodies, senile plaques, and neurofibrillary tangles are unclear. Recent work has shown that the apolipoprotein E4 allele, encoded on chromosome 19, is a risk factor for the development of Alzheimerís disease.64,65 Apoli-
poprotein E is normally present in the brain and plays a role in cholesterol transport. Only the E4 allele has been shown to be associated with Alzheimerís disease. It appears that there is no association between Parkinsonís disease and apolipoprotein E4.66,67 Apolipoprotein E4 allele frequencies are intermediate between Alzheimerís and Parkinsonís disease in those patients with senile dementia of the Lewy body type.67

It is unlikely that the coexistence of these two histopathologic processes is merely a coincidence. In 1993, Förstl and colleagues62 examined 65 cases of clinically diagnosed Alzheimerís disease. At the time of autopsy, 8 cases (12%) had diffuse neocortical Lewy bodies. Six of the 8 cases with diffuse Lewy bodies met at least minimal histopathologic criteria for Alzheimerís disease, and in 5 of the 8 cases severe parkinsonian rigidity eventually developed. The results of this study proved that the occurrence of diffuse Lewy body disease and Alzheimerís disease together is much higher than that which would be found in a control population. Bergeron and Pollanen68 studied a series of 150 cases of Alzheimerís disease along with 75 control cases. Thirty-seven patients (25%) with clinical Alzheimerís disease had Lewy bodies along with neurofibrillary tangles, as compared with only 5% of control patients. The majority of the 37 patients had primarily brain stem Lewy bodies; however, 5 patients also had numerous cortical Lewy bodies. Clearly, these studies along with others58-60 show that these two histopathologic changes occur together with greater frequency than would normally be expected by chance alone. It is now thought that dementia associated with Lewy body disease is second only to pure Alzheimerís disease as a cause of dementia in the elderly.

1. Lewy FH: Paralysis agitans. Pathologische Anatomie. Handbuch der Neurologie. Lewandowsky M (ed). Berlin, Germany, Springer-Verlag, 1912, pp 920-933

2. Forno LS: Pathology of Parkinsonís disease: the importance of the substantia nigra and Lewy bodies. Parkinsonís Disease. Stern GM (ed). Baltimore, Md, Johns Hopkins University Press, 1990, pp 185-238

3. Duffy PE, Tennyson VM: Phase and electron microscopic observations of Lewy bodies and melanin granules in the substantia nigra and locus coeruleus in Parkinsonís disease. J Neuropathol Exp Neurol 1965; 24:398-414

4. Forno LS, Norville RL: Ultrastructure of Lewy bodies in stellate ganglion. Acta Neuropathol 1976; 34:183-197

5. Hansen LA, Galasko D: Lewy body disease. Curr Opin Neurol Neurosurg 1992; 5:889-894

6. Schmidt ML, Murray J, Lee VM-Y, et al: Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol 1991; 139:53-65

7. Kosaka K: Lewy bodies in the cerebral cortex: report of three cases. Acta Neuropathol (Berl) 1978; 42:127-134

8. Yoshimura M: Cortical changes in the parkinsonian brain: a contribution to the delineation of ìdiffuse Lewy body disease.î J Neurol 1983; 229:17-32

9. Hill W, Lee VM-Y, Hurtig H, et al: Epitopes located in spatially separate domains of each neurofilament subunit are present in Parkinsonís disease Lewy bodies. J Comp Neurol 1991; 309:150-160

10. Schmidt ML, Murray J, Lee VM-Y, et al: Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol 1991; 139:53-65

11. Bancher C, Lassmann H, Budka H, et al: An antigenic profile of Lewy bodies: immunocytochemical indication for protein phosphorylation and ubiquitination. J Neuropathol Exp Neurol 1989; 48:81-93

12. Kuzuhara S, Mori H, Izumiyama N, et al: Lewy bodies are ubiquitinated. a light and electron microscopic immunocytochemical study. Acta Neuropathol (Berl) 1988; 75:345-353

13. Leigh P, Probst A, Gale G, et al: New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies. Acta Neuropathol (Berl) 1989; 79:61-72

14. Leestma JE, Andrews JM: The fine structure of the Marinesco body. Arch Pathol 1969; 88:431-436

15. Perry RH, Irving D, Tomlinson BE: Lewy body prevalence in the aging brain: relationship to neuropsychiatric disorders, Alzheimer-type pathology and catecholaminergic nuclei. J Neurol Sci 1991; 102:121

16. Newcastle NB: Degenerative diseases of the central nervous system. Textbook of Neuropathology. Davis RL, Robertson DM (eds). Baltimore, Md, Williams & Wilkins, 1991, pp 904-961

18. Jellinger K, Riederer P: Dementia in Parkinsonís disease and (pre)senile dementia of Alzheimer type: morphological aspects and changes in the intracerebral MAO activity. Adv Neurol 1984; 40:199-210

19. Korczyn AD: Parkinsonís disease. Psychopharmacology: The Fourth Generation of Progress. Bloom FE, Kupfer DJ (eds). New York, Raven Press, 1995, pp 1479-1484

20. Hughes AJ, Daniel SE, Blankson S, et al: A clinicopathologic study of 100 cases of Parkinsonís disease. Arch Neurol 1993; 50:140-148

21. Braak H, Braak E, Yilmazer D, et al: Amygdala pathology in Parkinsonís disease. Acta Neuropathol 1994; 88:493-500

22. Jager WA, Den Hartog, Bethlem J: The distribution of Lewy bodies of the central and autonomic nervous system in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 1960; 23:283-290

23. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science. New York, Elsevier Science Publishing Co, 3rd Ed, 1991, pp 606-607, 647-659, 863-865

24. Treves TA, Chandra V, Korczyn AD: Parkinsonís and Alzheimerís diseases: epidemiological comparison. Neuroepidemiology 1993; 12:336-349

25. Paddison RM, Griffith RP: Occurrence of Parkinsonís disease in black patients at Charity Hospital in New Orleans. Neurology 1993; 24:688-691

26. Marsden CD: Parkinsonís disease. Postgrad Med J 1992; 68:538-543

27. Langston JW, Ballard P, Tetried JW, et al: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219:970-980

28. Rossetti ZL, Sotgiu A, Sharp D, et al: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro. Biochem Pharmacol 1988; 37:4573-4574

29. Vyas I, Heikkila RE, Nicklas WJ: Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Inhibition of NAD-linked substrate oxidation by its metabolite 1-methyl-4-phenylpyridinium. J Neurochem 1986; 46:1501-1507

30. Sian J, Dexter DT, Lees AJ, et al: Alterations in glutathione levels in Parkinsonís disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 1994; 36:348-355

31. Sian J, Dexter DT, Lees AJ, et al: Glutathione-related enzymes in brain in Parkinsonís disease. Ann Neurol 1994; 36:356-361

32. Mann VM, Cooper JM, Daniel SE, et al: Complex I, iron, and ferritin in Parkinsonís disease substantia nigra. Ann Neurol 1994; 36:876-881

33. Nakano M: A possible mechanism of iron neurotoxicity. Eur Neurol 1993; 33(suppl):44-51

34. Schapira AHV: Evidence for mitochondrial dysfunction in Parkinsonís diseaseóa critical appraisal. Mov Disord 1994; 9:125-138

35. DiDonato S, Zeviani M, Giovannini P, et al: Respiratory chain and mitochondrial DNA in muscle and brain in Parkinsonís disease patients. Neurology 1993; 43:2262-2268

36. Dexter DT, Sian J, Rose S, et al: Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 1994; 35:38-44

37. Cardellach F, Martí MJ, Fernández-Solá J, et al: Mitochondrial respiratory chain activity in skeletal muscle from patients with Parkinsonís disease. Neurology 1993; 43:2258-2262

38. Tooyami I, Kawamata T, Walker D, et al: Loss of basic fibroblastic growth factor in substantia nigra neurons in Parkinsonís disease. Neurology 1993; 43:372-376

39. Moroo I, Yamada T, Makeno H, et al: Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinsonís disease. Acta Neuropathol 1994; 87:343-348

40. Vieregge P: Genetic factors in the etiology of idiopathic Parkinsonís disease. J Neural Transm 1994; 8:1-37

41. Lazzarini AM, Myers RH, Zimmerman TR Jr, et al: A clinical genetic study of Parkinsonís disease: evidence for dominant transmission. Neurology 1994; 44:499-506

42. Gasser T, Wszolek ZK, Trofatter J, et al: Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. Ann Neurol 1994; 36:387-396

43. Waters CH, Miller CA: Autosomal dominant Lewy body parkinsonism in a four-generation family. Ann Neurol 1994; 35:59-64

44. Golbe LI, DiIorio G, Bonavita V, et al: A large kindred with autosomal dominant Parkinsonís disease. Ann Neurol 1990; 27:276-282

45. Martin WE, Young WI, Anderson VE: Parkinsonís disease. a genetic study. Brain 1973; 96:495-506

46. Kondo K, Kurland LT: Parkinsonís disease. genetic analysis and evidence of a multifactorial etiology. Mayo Clin Proc 1973; 48:465-474

47. Payami H, Bernard S, Larsen K, et al: Genetic anticipation in Parkinsonís disease. Neurology 1995; 45:135-138

48. Johnson WG, Hodge SE, Duvoisin RC: Twin studies and the genetics of Parkinsonís disease. Mov Disord 1980; 5:187-194

49. Smith CAD, Gough AC, Leigh PN, et al: Debrisoquin hydroxylase gene polymorphism and susceptibility to Parkinsonís disease. Lancet 1992; 339:1375-1377

50. Gibb WRG, Luthert PJ, Janota I, et al: Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry 1992; 52:182-192

51. Yoshimura M: Cortical changes in the parkinsonism brain: a contribution to the delineation of ìdiffuse Lewy body disease.î J Neurol 1983; 229:17-32

52. Ikeda K, Ikeda S, Yoshimura T, et al: Idiopathic parkinsonism with Lewy-type inclusions in the cerebral cortex. a case report. Acta Neuropathol (Berl) 1978; 41:165-168

53. Kosaka K, Yoshimura M, Ikeda K, et al: Diffuse type of Lewy body disease: progressive dementia and abundant cortical Lewy bodies and senile changes of varying degreeóa new disease? Clin Neuropathol 1984; 3:185-192

54. Dickson DW, Davies P, Mayeux R, et al: Diffuse Lewy body disease. neuropathological and biochemical studies of six patients. Acta Neuropathol (Berl) 1987; 75:8-15

55. Ditter SM, Mirra SS: Neuropathologic and clinical features of Parkinsonís disease in Alzheimerís disease patients. Neurology 1987; 37:754-760

56. Byrne EJ, Lennox G, Lowe J, et al: Diffuse Lewy body disease: the clinical features. Adv Neurol 1990; 53:283-286

57. Kosaka K, Tsuchiya K, Yoshimura M: Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988; 7:299-305

58. Hansen L, Salmon D, Galasko D, et al: The Lewy body variant of Alzheimerís disease: a clinical and pathologic entity. Neurology 1990; 40:1-8

59. Hakim AM, Mathieson G: Dementia in Parkinsonís disease: a neuropathologic study. Neurology 1979; 29:1209-1214

60. Boller F, Mitzutani T, Roessmann U, et al: Parkinsonís disease, dementia, and Alzheimerís disease: clinicopathological correlations. Ann Neurol 1980; 7:329-335

61. Gibb WRG, Mann DMA, Mountjoy CQ, et al: A pathological study of the association between Lewy body disease and Alzheimerís disease. Adv Neurol 1990; 53:55-59

62. Förstl H, Burns A, Luthert P, et al: The Lewy body variant of Alzheimerís disease. clinical and pathological findings. Br J Psychiatry 1993; 162:385-392

63. Hansen LA, Masliah E, Terry RD, et al: A neuropathological subset of Alzheimerís disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol 1989; 78:194-201

64. Corder EH, Saunders AM, Strittmatter WJ, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimerís disease in late onset families. Science 1993; 261:921-923

65. Saunders AM, Strittmatter WJ, Schmechel D, et al: Association of apolipoprotein E allele (e4) with late onset familial and sporadic Alzheimerís disease. Neurology 1993; 43:1467-1472

66. Hansen LA, Galasko D, Samuel W, et al: Apolipoprotein-E e-4 is associated with increased neurofibrillary pathology in the Lewy body variant of Alzheimerís disease. Neurosci Lett 1994; 182:63-65

67. Hardy J, Crook R, Prihar G, et al: Senile dementia of the Lewy body type has an apolipoprotein E e4 allele frequency intermediate between controls and Alzheimerís disease. Neurosci Lett 1994; 182:1-2

68. Bergeron C, Pollanen M: Lewy bodies in Alzheimerís diseaseóone or two diseases? Alzheimerís Dis Assoc Disord 1989; 3:197-204